43 results on '"Cordova B"'
Search Results
2. Lipid Composition of the Liver Oil of Shark Species from the Caribbean and Gulf of California Waters
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Navarro-Garcia, G., Pacheco-Aguilar, R., Vallejo-Cordova, B., Ramirez-Suarez, J.C., and Bolaños, A.
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- 2000
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3. Experience on cellular selection of CD 133+ of bone marrow aspirates and the collection of peripheral blood hematopoietic progenitors for cardiac autologous cell therapy
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Ceron, W.M., Cordova, B., Carrillo, E., and Perez, I.
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- 2014
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4. ChemInform Abstract: The Synthesis and Evaluation of Cyclic Ureas as HIV Protease Inhibitors: Modifications of the P1/P1′ Residues.
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PATEL, M., BACHELER, L. T., RAYNER, M. M., CORDOVA, B. C., KLABE, R. M., ERICKSON-VIITANEN, S., and SEITZ, S. P.
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- 1998
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5. ChemInform Abstract: Potent Cyclic Urea HIV Protease Inhibitors with Benzofused Heterocycles as P2/P2′ Groups.
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RODGERS, J. D., JOHNSON, B. L., WANG, H., GREENBERG, R. A., ERICKSON-VIITANEN, S., KLABE, R. M., CORDOVA, B. C., RAYNER, M. M., LAM, G. N., and CHANG, C.-H.
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- 1997
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6. ChemInform Abstract: A Bis-(N-3-(1-hydroxy-1-methyl-ethyl)-benzyl)-cyclic Urea as a HIV Protease Inhibitor.
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WILKERSON, W. W., HOLLIS, A. Y., CHEATHAM, W. W., LAM, G. N., ERICKSON-VIITANEN, S., BACHELER, L., CORDOVA, B. C., KLABE, R. M., and MEEK, J. L.
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- 1996
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7. Alkaloids from Rauwolfia psychotrioides
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Hernán, E., Córdova, B., and Peña, Carmen Alicia
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- 1979
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8. Multidisciplinary Home-Based Rehabilitation Program for Individuals With Disabilities: Longitudinal Observational Study.
- Author
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Barría P, Andrade A, Gomez-Vargas D, Yelincic A, Roberti F, Bahamonde E, Aguilar R, and Cordova B
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Background: Disability affects a significant portion of the global population nowadays, necessitating innovative approaches to access rehabilitation processes. Home-based rehabilitation has emerged as a beneficial approach, offering comfort and context-specific therapy., Objective: This study aims to evaluate the impact of a multidisciplinary home-based rehabilitation program for individuals with moderate neuromusculoskeletal disabilities in terms of motor function and mood., Methods: A total of 270 participants with median age of 66 (IQR 20-98) years were recruited from the National Disability Registry of Chile. The intervention involved a multidisciplinary team composed of 49 health care professionals providing personalized treatment plans over 4 months (32 sessions for physical therapy, 8 sessions for occupational therapy, 4 sessions for nutrition, 8 sessions for psychology, and 4 sessions for nursing and podiatry). This program also included 2 medical evaluations (at the beginning and the end) to monitor clinical progress in terms of motor function and mental health, using the Berg Balance Scale and Beck Depression Inventory, respectively., Results: The home-based rehabilitation program showed significant improvements (P<.001) in motor function and balance with a reduction in fall risk. Specifically, the Berg Balance Scale score decreased close to 15% after the home-based rehabilitation program for all enrolled participants. On the other hand, depression levels showed no significant changes (P=.27), with percentages of variation less than 8% between the 2 assessed conditions. In this sense, participants remained with the same mild depression level (14 of 63) concerning the Beck Depression Inventory score., Conclusions: This study concludes that personalized home-based rehabilitation programs are effective in enhancing motor function and balance, particularly in individuals with neurological conditions. On the other hand, the findings in terms of mood advocate for further exploration of psychological support within such programs to enhance overall patient well-being., Trial Registration: ClinicalTrials.gov NCT06537791; https://clinicaltrials.gov/study/NCT06537791., (©Patricio Barría, Asterio Andrade, Daniel Gomez-Vargas, Alejandro Yelincic, Flavio Roberti, Eduardo Bahamonde, Rolando Aguilar, Bessie Cordova. Originally published in JMIR Rehabilitation and Assistive Technology (https://rehab.jmir.org), 16.10.2024.)
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- 2024
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9. Comparative Analysis of Ventilatory Responses during Stress Tests in Patients with Chronic Pain: Implications for Therapeutic Interventions.
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Barría P, Gaitán-Padilla M, Gomez-Vargas D, Cardenas Ampuero G, Gitterman K, Cordova B, Diaz CAR, and Roberti F
- Abstract
Understanding the differences in ventilatory responses during exercise between patients with fibromyalgia and those with other chronic pain disorders is crucial for developing effective therapeutic interventions, especially in exercise to identify the better physical therapy prescription. Both populations face unique challenges that impact their ability to engage in physical activity; yet, the underlying physiological responses can vary significantly. In this context, the methodology of this study entailed conducting a comparative analysis of the ventilatory response during exercise in patients with fibromyalgia and those with other chronic pain disorders. The experimental protocol included a total of 31 participants (n = 13 diagnosed with fibromyalgia and n = 18 diagnosed with other chronic pain conditions). All participants completed a stress test, where the ventilatory parameters were measured in three stages (i.e., resting, incremental exercise, and recovery). The results revealed significant differences (p<0.05) in ventilatory responses between both groups. Patients with fibromyalgia exhibited reduced time for the aerobic threshold and a higher respiratory frequency in the anaerobic threshold compared to those with other chronic pain disorders. Furthermore, fibromyalgia patients demonstrated higher values in the ventilatory coefficient during the test and in the recovery stage. In conclusion, these differences underscore the need for tailored exercise programs that specifically address the unique ventilatory challenges faced by fibromyalgia patients to improve their physical function and overall quality of life.
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- 2024
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10. PHARMACOKINETICS AND EFFICACY OF A SINGLE TOPICAL DOSE OF EPRINOMECTIN IN GIRAFFE ( GIRAFFA SPP.).
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Richardson A, Dadone L, Johnston M, Bapodra-Villaverde P, Schilz A, Contreras E, Rivas A, Schwenzer S, Zec S, Cordova B, Ferguson S, Banks KE, Gustafson DL, and Sadar MJ
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- Male, Humans, Female, Animals, Cattle, Prospective Studies, Administration, Topical, Ivermectin therapeutic use, Anthelmintics therapeutic use, Giraffes, Ivermectin analogs & derivatives
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Growing resistance to current antiparasitic medications, both in livestock and in zoological species under human care, makes it imperative to evaluate available drugs on the market, such as eprinomectin. In this prospective study, five males and one female of reticulated ( Giraffa reticulata ; n = 2), Masai ( Giraffa tippelskirchii ; n = 1), Nubian ( Giraffa camelopardalis ; n = 2), and hybrid subspecies ( n = 1) of giraffe, received 1.5 mg/kg eprinomectin topically along the dorsum. Using high-performance liquid chromatography, concentrations of eprinomectin in plasma samples collected at 0, 4, 24, and 48 h, and 7, 14, 21, and 28 d were evaluated following drug administration. Complete blood cell counts and biochemistry panels were performed before ( n = 6) and after ( n = 3) eprinomectin administration. Samples for modified double centrifugal fecal flotation ( n = 6) were evaluated prior to eprinomectin administration to evaluate for endoparasites and were repeated after the study ( n = 5). Noncompartmental pharmacokinetic analysis was applied to the data. The observed maximum plasma concentration was 11.45 ng/ml and the time of observed maximum concentration was 2.67 d. The mean terminal half-life was 5.16 d. No adverse effects were observed related to eprinomectin administration and no blood work changes were observed. Parasite loads decreased ( n = 3) or did not change ( n = 2) after eprinomectin administration. The mean peak plasma concentration of eprinomectin in giraffe was similar to that achieved in cattle, despite using three times the dose.
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- 2024
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11. CoproID predicts the source of coprolites and paleofeces using microbiome composition and host DNA content.
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Borry M, Cordova B, Perri A, Wibowo M, Prasad Honap T, Ko J, Yu J, Britton K, Girdland-Flink L, Power RC, Stuijts I, Salazar-García DC, Hofman C, Hagan R, Samdapawindé Kagoné T, Meda N, Carabin H, Jacobson D, Reinhard K, Lewis C, Kostic A, Jeong C, Herbig A, Hübner A, and Warinner C
- Abstract
Shotgun metagenomics applied to archaeological feces (paleofeces) can bring new insights into the composition and functions of human and animal gut microbiota from the past. However, paleofeces often undergo physical distortions in archaeological sediments, making their source species difficult to identify on the basis of fecal morphology or microscopic features alone. Here we present a reproducible and scalable pipeline using both host and microbial DNA to infer the host source of fecal material. We apply this pipeline to newly sequenced archaeological specimens and show that we are able to distinguish morphologically similar human and canine paleofeces, as well as non-fecal sediments, from a range of archaeological contexts., Competing Interests: The authors declare that they have no competing interests., (© 2020 Borry et al.)
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- 2020
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12. Comparative analysis of the boundary layer filtering of odor signals in the amblypygid (whip spider) species Paraphrynus laevifrons and Phrynus marginemaculatus.
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Moore ME, Weighman KK, Steele AN, Cordova B, and Moore PA
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- Animals, Species Specificity, Air, Animal Communication, Arachnida physiology, Odorants analysis
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Amblypygids use a pair of modified walking legs (antenniform) as chemosensory and mechanosensory appendages. At the tip of these legs are covered in chemosensory sensilla, which the animals use to sample odor stimuli in their environment by moving the antenniform leg through the air. We designed a set of experiments to measure the filtering effect that aerodynamic boundary layers have on the temporal and spatial structure of chemical stimuli. In addition, two different species of amblypygids (Paraphrynus laevifrons and Phrynus marginemaculatus) that live in two distinct habitats were used for a comparative analysis. Pulses of a tracer molecule were quantified at different distances and flow velocities using an electrochemical detection system. Temporal attributes of the chemical pulses were extracted and were statistically compared across velocities, distances from the appendage, and the two species. Overall, the boundary layer significantly decreased the concentration and increased the duration of pulses for both species. This filtering effect was more pronounced for P. marginemaculatus than P. laevifrons, as the chemical signal was lower in concentration and longer in duration at any distance from the antenniform leg. It is speculated that the difference in boundary layer filtering, as a function of appendage morphology, is tuned to the different types of odor plumes in these animals' native habitats., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
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- 2020
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13. ThiN as a Versatile Domain of Transcriptional Repressors and Catalytic Enzymes of Thiamine Biosynthesis.
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Hwang S, Cordova B, Abdo M, Pfeiffer F, and Maupin-Furlow JA
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- Amino Acid Sequence, Archaeal Proteins genetics, DNA, Archaeal genetics, Models, Molecular, Molecular Structure, Nucleic Acid Conformation, Protein Binding, Protein Conformation, Purines chemistry, Purines metabolism, Thiamine chemistry, Archaeal Proteins metabolism, Gene Expression Regulation, Archaeal physiology, Haloferax volcanii metabolism, Thiamine biosynthesis, Transcription Factors physiology
- Abstract
Thiamine biosynthesis is commonly regulated by a riboswitch mechanism; however, the enzymatic steps and regulation of this pathway in archaea are poorly understood. Haloferax volcanii , one of the representative archaea, uses a eukaryote-like Thi4 (thiamine thiazole synthase) for the production of the thiazole ring and condenses this ring with a pyrimidine moiety synthesized by an apparent bacterium-like ThiC (2-methyl-4-amino-5-hydroxymethylpyrimidine [HMP] phosphate synthase) branch. Here we found that archaeal Thi4 and ThiC were encoded by leaderless transcripts, ruling out a riboswitch mechanism. Instead, a novel ThiR transcription factor that harbored an N-terminal helix-turn-helix (HTH) DNA binding domain and C-terminal ThiN (TMP synthase) domain was identified. In the presence of thiamine, ThiR was found to repress the expression of thi4 and thiC by a DNA operator sequence that was conserved across archaeal phyla. Despite having a ThiN domain, ThiR was found to be catalytically inactive in compensating for the loss of ThiE (TMP synthase) function. In contrast, bifunctional ThiDN, in which the ThiN domain is fused to an N-terminal ThiD (HMP/HMP phosphate [HMP-P] kinase) domain, was found to be interchangeable for ThiE function and, thus, active in thiamine biosynthesis. A conserved Met residue of an extended α-helix near the active-site His of the ThiN domain was found to be important for ThiDN catalytic activity, whereas the corresponding Met residue was absent and the α-helix was shorter in ThiR homologs. Thus, we provide new insight into residues that distinguish catalytic from noncatalytic ThiN domains and reveal that thiamine biosynthesis in archaea is regulated by a transcriptional repressor, ThiR, and not by a riboswitch. IMPORTANCE Thiamine pyrophosphate (TPP) is a cofactor needed for the enzymatic activity of many cellular processes, including central metabolism. In archaea, thiamine biosynthesis is an apparent chimera of eukaryote- and bacterium-type pathways that is not well defined at the level of enzymatic steps or regulatory mechanisms. Here we find that ThiN is a versatile domain of transcriptional repressors and catalytic enzymes of thiamine biosynthesis in archaea. Our study provides new insight into residues that distinguish catalytic from noncatalytic ThiN domains and reveals that archaeal thiamine biosynthesis is regulated by a ThiN domain transcriptional repressor, ThiR, and not by a riboswitch., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
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14. Conserved active site cysteine residue of archaeal THI4 homolog is essential for thiamine biosynthesis in Haloferax volcanii.
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Hwang S, Cordova B, Chavarria N, Elbanna D, McHugh S, Rojas J, Pfeiffer F, and Maupin-Furlow JA
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- Archaeal Proteins genetics, Biosynthetic Pathways genetics, Catalytic Domain, Cysteine genetics, Gene Deletion, Genetic Complementation Test, Haloferax volcanii enzymology, Haloferax volcanii genetics, Haloferax volcanii growth & development, Archaeal Proteins metabolism, Cysteine metabolism, Haloferax volcanii metabolism, Thiamine biosynthesis
- Abstract
Background: Thiamine (vitamin B1) is synthesized de novo by certain yeast, fungi, plants, protozoans, bacteria and archaea. The pathway of thiamine biosynthesis by archaea is poorly understood, particularly the route of sulfur relay to form the thiazole ring. Archaea harbor structural homologs of both the bacterial (ThiS-ThiF) and eukaryotic (THI4) proteins that mobilize sulfur to thiazole ring precursors by distinct mechanisms., Results: Based on comparative genome analysis, halophilic archaea are predicted to synthesize the pyrimidine moiety of thiamine by the bacterial pathway, initially suggesting that also a bacterial ThiS-ThiF type mechanism for synthesis of the thiazole ring is used in which the sulfur carrier ThiS is first activated by ThiF-catalyzed adenylation. The only ThiF homolog of Haloferax volcanii (UbaA) was deleted but this had no effect on growth in the absence of thiamine. Usage of the eukaryotic THI4-type sulfur relay was initially considered less likely for thiamine biosynthesis in archaea, since the active-site cysteine residue of yeast THI4p that donates the sulfur to the thiazole ring by a suicide mechanism is replaced by a histidine residue in many archaeal THI4 homologs and these are described as D-ribose-1,5-bisphosphate isomerases. The THI4 homolog of the halophilic archaea, including Hfx. volcanii (HVO_0665, HvThi4) was found to differ from that of methanogens and thermococci by having a cysteine residue (Cys165) corresponding to the conserved active site cysteine of yeast THI4p (Cys205). Deletion of HVO_0665 generated a thiamine auxotroph that was trans-complemented by a wild-type copy of HVO_0665, but not the modified gene encoding an HvThi4 C165A variant., Conclusions: Based on our results, we conclude that the archaeon Hfx. volcanii uses a yeast THI4-type mechanism for sulfur relay to form the thiazole ring of thiamine. We extend this finding to a relatively large group of archaea, including haloarchaea, ammonium oxidizing archaea, and some methanogen and Pyrococcus species, by observing that these organisms code for THI4 homologs that have a conserved active site cysteine residue which is likely used in thiamine biosynthesis. Thus, archaeal members of IPR002922 THI4 family that have a conserved cysteine active site should be reexamined for a function in thiamine biosynthesis.
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- 2014
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15. Drug design with a new transition state analog of the hydrated carbonyl: silicon-based inhibitors of the HIV protease.
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Chen CA, Sieburth SM, Glekas A, Hewitt GW, Trainor GL, Erickson-Viitanen S, Garber SS, Cordova B, Jeffry S, and Klabe RM
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- Cells, Cultured, Humans, Models, Molecular, Drug Design, HIV Protease Inhibitors chemistry, HIV Protease Inhibitors pharmacology, HIV-1 drug effects, Organosilicon Compounds chemistry, Organosilicon Compounds pharmacology
- Abstract
Background: Silicon is the element most similar to carbon, and bioactive organosilanes have therefore been of longstanding interest. Design of bioactive organosilanes has often involved a systematic replacement of a bioactive molecule's stable carbon atoms with silicon. Silanediols, which are best known as unstable precursors of the robust and ubiquitous silicone polymers, have the potential to mimic an unstable carbon, the hydrated carbonyl. As a bioisostere of the tetrahedral intermediate of amide hydrolysis, a silanediol could act as a transition state analog inhibitor of protease enzymes., Results: Silanediol analogs of a carbinol-based inhibitor of the HIV protease were prepared as single enantiomers, with up to six stereogenic centers. As inhibitors of this aspartic protease, the silanediols were nearly equivalent to both their carbinol analogs and indinavir, a current treatment for AIDS, with low nanomolar K(i) values. IC(90) data from a cell culture assay mirrored the K(i) data, demonstrating that the silanediols can also cross cell membranes and deliver their antiviral effects., Conclusions: In their first evaluation as inhibitors of an aspartic protease, silanediol peptidomimetics have been found to be nearly as potent as currently available pharmaceutical agents, in enzyme and cell protection assays. These neutral, cell-permeable transition state analogs therefore provide a novel foundation for the design of therapeutic agents.
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- 2001
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16. DPC 681 and DPC 684: potent, selective inhibitors of human immunodeficiency virus protease active against clinically relevant mutant variants.
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Kaltenbach RF 3rd, Trainor G, Getman D, Harris G, Garber S, Cordova B, Bacheler L, Jeffrey S, Logue K, Cawood P, Klabe R, Diamond S, Davies M, Saye J, Jona J, and Erickson-Viitanen S
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- Administration, Oral, Animals, Blood Proteins metabolism, Dogs, Drug Resistance, Microbial, Female, Genotype, HIV Protease Inhibitors pharmacokinetics, Humans, Injections, Intravenous, Male, Protein Binding, Sulfonamides pharmacokinetics, HIV Infections virology, HIV Protease Inhibitors pharmacology, HIV-1 drug effects, Sulfonamides pharmacology
- Abstract
Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of many highly active antiretroviral therapy regimens. However, development of phenotypic and/or genotypic resistance can occur, including cross-resistance to other PIs. Development of resistance takes place because trough levels of free drug are inadequate to suppress preexisting resistant mutant variants and/or to inhibit de novo-generated resistant mutant variants. There is thus a need for new PIs, which are more potent against mutant variants of HIV and show higher levels of free drug at the trough. We have optimized a series of substituted sulfonamides and evaluated the inhibitors against laboratory strains and clinical isolates of HIV type 1 (HIV-1), including viruses with mutations in the protease gene. In addition, serum protein binding was determined to estimate total drug requirements for 90% suppression of virus replication (plasma IC(90)). Two compounds resulting from our studies, designated DPC 681 and DPC 684, are potent and selective inhibitors of HIV protease with IC(90)s for wild-type HIV-1 of 4 to 40 nM. DPC 681 and DPC 684 showed no loss in potency toward recombinant mutant HIVs with the D30N mutation and a fivefold or smaller loss in potency toward mutant variants with three to five amino acid substitutions. A panel of chimeric viruses constructed from clinical samples from patients who failed PI-containing regimens and containing 5 to 11 mutations, including positions 10, 32, 46, 47, 50, 54, 63, 71, 82, 84, and 90 had mean IC(50) values of <20 nM for DPC 681 and DPC 681, respectively. In contrast, marketed PIs had mean IC(50) values ranging from 200 nM (amprenavir) to >900 nM (nelfinavir).
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- 2001
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17. Synthesis and evaluation of novel quinolinones as HIV-1 reverse transcriptase inhibitors.
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Patel M, McHugh RJ Jr, Cordova BC, Klabe RM, Bacheler LT, Erickson-Viitanen S, and Rodgers JD
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- Antiviral Agents chemical synthesis, Drug Resistance genetics, HIV-1 genetics, Humans, Inhibitory Concentration 50, Mutation genetics, Quinolones chemical synthesis, Antiviral Agents pharmacology, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, Quinolones pharmacology
- Abstract
A series of 4,4-disubstituted quinolinones was prepared and evaluated as HIV-1 reverse transcriptase inhibitors. The C-3 substituted compound 9h displayed improved antiviral activity against clinically significant single (K103N) and double (K103N/L100I) mutant viruses.
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- 2001
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18. 4,1-Benzoxazepinone analogues of efavirenz (Sustiva) as HIV-1 reverse transcriptase inhibitors.
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Cocuzza AJ, Chidester DR, Cordova BC, Klabe RM, Jeffrey S, Diamond S, Weigelt CA, Ko SS, Bacheler LT, Erickson-Viitanen SK, and Rodgers JD
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- Alkynes, Animals, Benzoxazines, Cyclopropanes, HIV Reverse Transcriptase genetics, Humans, Macaca mulatta, Oxazines chemistry, Oxazines pharmacokinetics, Protein Binding, Quinazolines chemistry, Quinazolines pharmacokinetics, Quinazolines pharmacology, Quinazolinones, Reverse Transcriptase Inhibitors chemistry, Reverse Transcriptase Inhibitors pharmacokinetics, Structure-Activity Relationship, HIV Reverse Transcriptase antagonists & inhibitors, Oxazines pharmacology, Reverse Transcriptase Inhibitors pharmacology
- Abstract
A series of 4,1-benzoxazepinone analogues of efavirenz (Sustiva) as potent NNRTIs has been discovered. The cis-3-alkylbenzoxazepinones are more potent then the trans isomers and can be synthesized preferentially by a novel stereoselective cyclization. The best compounds are potent orally bioavailable inhibitors of both wild-type HIV-1 and its clinically relevant K103N mutant virus, but are highly protein-bound in human plasma.
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- 2001
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19. Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy.
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Bacheler L, Jeffrey S, Hanna G, D'Aquila R, Wallace L, Logue K, Cordova B, Hertogs K, Larder B, Buckery R, Baker D, Gallagher K, Scarnati H, Tritch R, and Rizzo C
- Subjects
- Alkynes, Amino Acid Substitution, Anti-HIV Agents therapeutic use, Benzoxazines, Cells, Cultured, Clinical Trials, Phase II as Topic, Cohort Studies, Cyclopropanes, Delavirdine pharmacology, Drug Resistance, Microbial, Drug Resistance, Multiple, Genotype, HIV Infections drug therapy, HIV Reverse Transcriptase genetics, HIV-1 enzymology, HIV-1 genetics, Humans, Leukocytes, Mononuclear virology, Microbial Sensitivity Tests, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, Nevirapine pharmacology, Oxazines therapeutic use, Reverse Transcriptase Inhibitors therapeutic use, Treatment Failure, Anti-HIV Agents pharmacology, HIV Infections virology, HIV-1 drug effects, Oxazines pharmacology, Reverse Transcriptase Inhibitors pharmacology
- Abstract
Efavirenz (also known as DMP 266 or SUSTIVA) is a potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and of HIV-1 replication in vitro and in vivo. Most patients on efavirenz-containing regimens have sustained antiviral responses; however, rebounds in plasma viral load have been observed in some patients in association with the emergence of mutant strains of HIV-1. Virus isolates from the peripheral blood mononuclear cells (PBMCs) of patients with such treatment failures, as well as recombinant viruses incorporating viral sequences derived from patient plasma, show reduced in vitro susceptibility to efavirenz in association with mutations in the RT gene encoding K103N, Y188L, or G190S/E substitutions. Patterns of RT gene mutations and in vitro susceptibility were similar in plasma virus and in viruses isolated from PBMCs. Variant strains of HIV-1 constructed by site-directed mutagenesis confirmed the role of K103N, G190S, and Y188L substitutions in reduced susceptibility to efavirenz. Further, certain secondary mutations (V106I, V108I, Y181C, Y188H, P225H, and F227L) conferred little resistance to efavirenz as single mutations but enhanced the level of resistance of viruses carrying these mutations in combination with K103N or Y188L. Viruses with K103N or Y188L mutations, regardless of the initial selecting nonnucleoside RT inhibitor (NNRTI), exhibited cross-resistance to all of the presently available NNRTIs (efavirenz, nevirapine, and delavirdine). Some virus isolates from nevirapine or delavirdine treatment failures that lacked K103N or Y188L mutations remained susceptible to efavirenz in vitro, although the clinical significance of this finding is presently unclear.
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- 2001
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20. Synthesis and evaluation of efavirenz (Sustiva) analogues as HIV-1 reverse transcriptase inhibitors: replacement of the cyclopropylacetylene side chain.
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Cocuzza AJ, Chidester DR, Cordova BC, Jeffrey S, Parsons RL, Bacheler LT, Erickson-Viitanen S, Trainor GL, and Ko SS
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- Alkynes, Benzoxazines, Cyclopropanes, HIV Reverse Transcriptase genetics, Mutation, Structure-Activity Relationship, Anti-HIV Agents chemical synthesis, Anti-HIV Agents pharmacology, HIV Reverse Transcriptase antagonists & inhibitors, Oxazines chemical synthesis, Oxazines pharmacology, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors pharmacology
- Abstract
Two series of efavirenz analogues have been developed: one in which the cyclopropane ring has been replaced by small heterocycles and another in which the entire acetylenic side chain has been replaced by alkyloxy groups. Several members of both series show equivalent potency to efavirenz against both wild-type virus and the key K103N mutant.
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- 2001
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21. Synthesis and biological activities of potential metabolites of the non-nucleoside reverse transcriptase inhibitor efavirenz.
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Markwalder JA, Christ DD, Mutlib A, Cordova BC, Klabe RM, and Seitz SP
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- Alkynes, Animals, Antiviral Agents chemistry, Benzoxazines, Biotransformation, Cyclopropanes, Humans, Molecular Structure, Oxazines pharmacology, Reverse Transcriptase Inhibitors chemistry, Antiviral Agents chemical synthesis, Antiviral Agents pharmacology, Oxazines metabolism, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors pharmacology
- Abstract
Studies on the biotransformation of the clinically important non-nucleoside reverse transcriptase inhibitor efavirenz have shown that oxidation and secondary conjugation are important components of the processing of this molecule in vivo. We have synthesized metabolites of efavirenz to confirm their structure and to evaluate their activity as antivirals.
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- 2001
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22. Trifluoromethyl-containing 3-alkoxymethyl- and 3-aryloxymethyl-2-pyridinones are potent inhibitors of HIV-1 non-nucleoside reverse transcriptase.
- Author
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Corbett JW, Kresge KJ, Pan S, Cordova BC, Klabe RM, Rodgers JD, and Erickson-Viitanen SK
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- Anti-HIV Agents pharmacology, Combinatorial Chemistry Techniques, Cytopathogenic Effect, Viral drug effects, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Fluorine chemistry, HIV Reverse Transcriptase genetics, HIV-1 drug effects, HIV-1 genetics, Inhibitory Concentration 50, Mutation, Pyridones chemical synthesis, Structure-Activity Relationship, Anti-HIV Agents chemical synthesis, HIV Reverse Transcriptase antagonists & inhibitors, Pyridones pharmacology
- Abstract
3-Alkoxymethyl- and 3-aryloxymethyl-2-pyridinones were synthesized and evaluated for activity as non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1. It was found that several compounds were potent inhibitors of HIV-1 with the most potent compound 24 exhibiting an IC90 = 32 nM. Compound 24 also possessed a potent resistance profile as demonstrated by submicromolar IC90s against several clinically meaningful mutant virus strains.
- Published
- 2001
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23. 3,3a-Dihydropyrano[4,3,2-de]quinazolin-2(1H)-ones are potent non-nucleoside reverse transcriptase inhibitors.
- Author
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Corbett JW, Pan S, Markwalder JA, Cordova BC, Klabe RM, Garber S, Rodgers JD, and Erickson-Viitanen SK
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- Binding Sites, Combinatorial Chemistry Techniques, Drug Resistance, HIV Reverse Transcriptase genetics, Heterocyclic Compounds, 2-Ring chemical synthesis, Heterocyclic Compounds, 2-Ring pharmacology, Heterocyclic Compounds, 3-Ring chemical synthesis, Heterocyclic Compounds, 3-Ring pharmacology, Humans, Inhibitory Concentration 50, Models, Molecular, Point Mutation, Pyrans chemical synthesis, Quinazolines chemical synthesis, Reverse Transcriptase Inhibitors pharmacology, Structure-Activity Relationship, HIV Reverse Transcriptase antagonists & inhibitors, Pyrans pharmacology, Quinazolines pharmacology, Reverse Transcriptase Inhibitors chemical synthesis
- Abstract
A series of unique 3,3a-dihydropyrano[4,3,2-de]quinazolin-2(1H)-ones and a 2a,5-dihydro-2H-thieno[4,3,2-de]quinazo-line-4(3H)-thione were found to be HIV-1 non-nucleoside reverse transcriptase inhibitors. One of these compounds, as the racemate, possessed an IC90 = 4.6 nM against wild-type virus in a whole cell antiviral assay and had an IC90 = 76 and 897 nM against the clinically significant K103N and K103N/L100I mutant viruses, respectively.
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- 2001
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24. Synthesis and evaluation of quinoxalinones as HIV-1 reverse transcriptase inhibitors.
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Patel M, McHugh RJ Jr, Cordova BC, Klabe RM, Erickson-Viitanen S, Trainor GL, and Rodgers JD
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- Drug Evaluation, HIV Reverse Transcriptase drug effects, Quinoxalines chemical synthesis, Quinoxalines pharmacology, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors pharmacology
- Abstract
A series of 3,3-disubstituted quinoxalinones was prepared and evaluated as HIV-1 reverse transcriptase inhibitors. The N-allyl (6b and 6f), N-cyclopropylmethyl (6a, 6g, 6h, and 6k) and N-carboalkoxy (6m-6y) substituted compounds displayed activity comparable or better than Efavirenz and GW420867X.
- Published
- 2000
- Full Text
- View/download PDF
25. Inhibition of clinically relevant mutant variants of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors.
- Author
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Corbett JW, Ko SS, Rodgers JD, Gearhart LA, Magnus NA, Bacheler LT, Diamond S, Jeffrey S, Klabe RM, Cordova BC, Garber S, Logue K, Trainor GL, Anderson PS, and Erickson-Viitanen SK
- Subjects
- Alkynes, Anti-HIV Agents blood, Anti-HIV Agents pharmacology, Benzoxazines, Blood Proteins metabolism, Cyclopropanes, HIV-1 genetics, Humans, Molecular Structure, Oxazines blood, Oxazines pharmacology, Protein Binding, Quinazolines blood, Quinazolines pharmacology, Reverse Transcriptase Inhibitors blood, Reverse Transcriptase Inhibitors pharmacology, Structure-Activity Relationship, Virus Replication drug effects, Anti-HIV Agents chemical synthesis, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, Mutation, Quinazolines chemical synthesis, Reverse Transcriptase Inhibitors chemical synthesis
- Abstract
A series of 4-alkenyl and 4-alkynyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones were found to be potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) of human immunodeficiency virus type-1 (HIV-1). The 4-alkenyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 082 and DPC 083 and the 4-alkynyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 961 and DPC 963 were found to exhibit low nanomolar potency toward wild-type RF virus (IC(90) = 2.0, 2.1, 2.0, and 1.3 nM, respectively) and various single and many multiple amino acid substituted HIV-1 mutant viruses. The increased potency is combined with favorable plasma serum protein binding as demonstrated by improvements in the percent free drug in human plasma when compared to efavirenz: 3.0%, 2.0%, 1.5%, 2. 8%, and 0.2-0.5% for DPC 082, DPC 083, DPC 961, DPC 963, and efavirenz, respectively.
- Published
- 2000
- Full Text
- View/download PDF
26. Novel 2,2-dioxide-4,4-disubstituted-1,3-H-2,1,3-benzothiadiazines as non-nucleoside reverse transcriptase inhibitors.
- Author
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Corbett JW, Gearhart LA, Ko SS, Rodgers JD, Cordova BC, Klabe RM, and Erickson-Viitanen SK
- Subjects
- Benzothiadiazines pharmacology, HIV-1 enzymology, Humans, Molecular Structure, Reverse Transcriptase Inhibitors pharmacology, Benzothiadiazines chemical synthesis, Reverse Transcriptase Inhibitors chemical synthesis
- Abstract
Benzothiadiazine non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV have been synthesized via a novel process to afford active inhibitors, with the most potent compound exhibiting an IC90 = 180 nM in a whole cell assay. The 2,2-dioxide-1H-2,1,3-benzothiadiazine ring system was constructed in one step from 2-amino-5-chlorobenzonitrile.
- Published
- 2000
- Full Text
- View/download PDF
27. Synthesis and evaluation of benzoxazinones as HIV-1 reverse transcriptase inhibitors. Analogs of Efavirenz (SUSTIVA).
- Author
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Patel M, McHugh RJ Jr, Cordova BC, Klabe RM, Erickson-Viitanen S, Trainor GL, and Ko SS
- Subjects
- Alkynes, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, Benzoxazines, Cyclopropanes, Drug Evaluation, Preclinical, HIV Reverse Transcriptase drug effects, Oxazines pharmacology, Reverse Transcriptase Inhibitors chemistry, Reverse Transcriptase Inhibitors pharmacology, Structure-Activity Relationship, Anti-HIV Agents chemical synthesis, Oxazines chemical synthesis, Oxazines chemistry, Reverse Transcriptase Inhibitors chemical synthesis
- Abstract
Two series of benzoxazinones differing in the aromatic substitution pattern were prepared and evaluated as HIV-1 reverse transcriptase inhibitors. The 5-fluoro (5a-d) and 6-nitro (5e-h) substituted compounds displayed activity comparable or better than Efavirenz, the lead structure of the series.
- Published
- 1999
- Full Text
- View/download PDF
28. Unsymmetrical cyclic ureas as HIV-1 protease inhibitors: novel biaryl indazoles as P2/P2' substituents.
- Author
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Patel M, Rodgers JD, McHugh RJ Jr, Johnson BL, Cordova BC, Klabe RM, Bacheler LT, Erickson-Viitanen S, and Ko SS
- Subjects
- Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, HIV Protease drug effects, HIV Protease Inhibitors pharmacology, HIV-1 enzymology, Urea pharmacology, HIV Protease Inhibitors chemistry, Urea chemistry
- Abstract
The preparation of unsymmetrical cyclic ureas bearing novel biaryl indazoles as P2/P2' substituents was undertaken, utilizing a Suzuki coupling reaction as the key step. Compound 6i was equipotent to the lead compound of the series SE063.
- Published
- 1999
- Full Text
- View/download PDF
29. Synthesis and evaluation of analogs of Efavirenz (SUSTIVA) as HIV-1 reverse transcriptase inhibitors.
- Author
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Patel M, Ko SS, McHugh RJ Jr, Markwalder JA, Srivastava AS, Cordova BC, Klabe RM, Erickson-Viitanen S, Trainor GL, and Seitz SP
- Subjects
- Alkynes, Anti-HIV Agents pharmacology, Benzoxazines, Cyclopropanes, Molecular Structure, Oxazines pharmacology, Reverse Transcriptase Inhibitors pharmacology, Structure-Activity Relationship, Anti-HIV Agents chemical synthesis, HIV-1, Oxazines chemical synthesis, Oxazines chemistry, Reverse Transcriptase Inhibitors chemical synthesis
- Abstract
Efavirenz (SUSTIVA) is a potent non-nucleoside reverse transcriptase inhibitor. Due to the observation of breakthrough mutations of the reverse transcriptase enzyme during Efavirenz therapy, we sought to develop an optimized second generation series. To that end, SAR of the substituents on the aromatic ring was undertaken and the results are summarized here. The 5,6-difluoro (4f) and the 6-methoxy (4m) substituted benzoxazinones were determined to be equipotent, and as a result such substitution patterns will be incorporated in second generation scaffolds.
- Published
- 1999
- Full Text
- View/download PDF
30. Increased antiviral activity of cyclic urea HIV protease inhibitors by modifying the P1/P1' substituents.
- Author
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Kaltenbach RF 3rd, Klabe RM, Cordova BC, and Seitz SP
- Subjects
- Drug Design, HIV Protease Inhibitors chemistry, HIV Protease Inhibitors pharmacology, Structure-Activity Relationship, Urea chemical synthesis, Urea pharmacology, HIV Protease Inhibitors chemical synthesis, Urea analogs & derivatives
- Abstract
A series of alkyl substituted P1/P1' analogs was prepared in an attempt to increase translation of the 3-aminoindazole class of HIV protease inhibitors. Increasing the lipophilicity of the P1/P1' residues dramatically improved translation of enzyme activity to antiviral activity in the whole cell assay.
- Published
- 1999
- Full Text
- View/download PDF
31. Design and selection of DMP 850 and DMP 851: the next generation of cyclic urea HIV protease inhibitors
- Author
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Rodgers JD, Lam PY, Johnson BL, Wang H, Ko SS, Seitz SP, Trainor GL, Anderson PS, Klabe RM, Bacheler LT, Cordova B, Garber S, Reid C, Wright MR, Chang CH, and Erickson-Viitanen S
- Published
- 1998
- Full Text
- View/download PDF
32. Nonsymmetric P2/P2' cyclic urea HIV protease inhibitors. Structure-activity relationship, bioavailability, and resistance profile of monoindazole-substituted P2 analogues.
- Author
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De Lucca GV, Kim UT, Liang J, Cordova B, Klabe RM, Garber S, Bacheler LT, Lam GN, Wright MR, Logue KA, Erickson-Viitanen S, Ko SS, and Trainor GL
- Subjects
- Administration, Oral, Animals, Azepines pharmacology, Biological Availability, Cell Line, Chromatography, High Pressure Liquid, Dogs, Drug Design, Drug Resistance, Microbial, HIV-1 drug effects, HIV-1 genetics, Mutation, RNA, Viral biosynthesis, Ritonavir pharmacology, Structure-Activity Relationship, Transcription, Genetic, Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, HIV Protease Inhibitors chemical synthesis, HIV Protease Inhibitors chemistry, HIV Protease Inhibitors pharmacology, Indazoles chemical synthesis, Indazoles chemistry, Indazoles pharmacology, Urea analogs & derivatives, Urea chemical synthesis, Urea chemistry, Urea pharmacology
- Abstract
Using the structural information gathered from the X-ray structures of various cyclic urea/HIVPR complexes, we designed and synthesized many nonsymmetrical P2/P2'-substituted cyclic urea analogues. Our efforts concentrated on using an indazole as one of the P2 substituents since this group imparted enzyme (Ki) potency as well as translation into excellent antiviral (IC90) potency. The second P2 substituent was used to adjust the physical and chemical properties in order to maximize oral bioavailability. Using this approach several very potent (IC90 11 nM) and orally bioavailable (F% 93-100%) compounds were discovered (21, 22). However, the resistance profiles of these compounds were inadequate, especially against the double (I84V/V82F) and ritonavir-selected mutant viruses. Further modification of the second P2 substituent in order to increase H-bonding interactions with the backbone atoms of residues Asp 29, Asp 30, and Gly 48 led to analogues with much better resistance profiles. However, these larger analogues were incompatible with the apparent molecular weight requirements for good oral bioavailability of the cyclic urea class of HIVPR inhibitors (MW < 610).
- Published
- 1998
- Full Text
- View/download PDF
33. The synthesis of symmetrical and unsymmetrical P1/P1' cyclic ureas as HIV protease inhibitors.
- Author
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Patel M, Kaltenbach RF 3rd, Nugiel DA, McHugh RJ Jr, Jadhav PK, Bacheler LT, Cordova BC, Klabe RM, Erickson-Viitanen S, Garber S, Reid C, and Seitz SP
- Subjects
- Binding Sites, Biological Availability, Drug Design, HIV Protease chemistry, HIV Protease metabolism, HIV Protease Inhibitors chemistry, HIV Protease Inhibitors pharmacology, Hydrogen Bonding, Kinetics, Models, Molecular, Molecular Structure, Structure-Activity Relationship, Urea chemistry, Urea pharmacology, HIV Protease Inhibitors chemical synthesis, Urea analogs & derivatives, Urea chemical synthesis
- Abstract
Cyclic urea SD146, a potent HIV protease inhibitor bearing a flat resistance profile, possessed poor solubility and bioavailability, which precluded further development of the compound. In an effort to improve upon the pharmacokinetic profile of the compound, several analogs modified at the P1/P1' residues were prepared and evaluated. Several of those compounds displayed significant improvement of physical properties.
- Published
- 1998
- Full Text
- View/download PDF
34. Potent cyclic urea HIV protease inhibitors with 3-aminoindazole P2/P2' groups.
- Author
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Rodgers JD, Johnson BL, Wang H, Erickson-Viitanen S, Klabe RM, Bacheler L, Cordova BC, and Chang CH
- Subjects
- Crystallography, X-Ray, Drug Design, HIV Protease chemistry, HIV Protease Inhibitors chemical synthesis, HIV Protease Inhibitors pharmacology, Indazoles pharmacology, Indicators and Reagents, Models, Molecular, Molecular Structure, Structure-Activity Relationship, Urea chemistry, Urea pharmacology, HIV Protease metabolism, HIV Protease Inhibitors chemistry, Indazoles chemistry, Urea analogs & derivatives
- Abstract
Cyclic ureas containing 3-aminoindazole P2/P2' groups are extremely potent inhibitors of HIV protease. The parent 3-aminoindazole 6 showed a Ki < 0.01 nM but poor translation of enzyme activity to antiviral activity was observed. A series of 3-alkylaminoindazoles revealed that translation improved with increasing lipophilicity. An X-ray crystal structure of 6 bound to HIV protease was obtained.
- Published
- 1998
- Full Text
- View/download PDF
35. The synthesis and evaluation of cyclic ureas as HIV protease inhibitors: modifications of the P1/P1' residues.
- Author
-
Patel M, Bacheler LT, Rayner MM, Cordova BC, Klabe RM, Erickson-Viitanen S, and Seitz SP
- Subjects
- Antiviral Agents chemistry, Antiviral Agents pharmacology, Azepines pharmacology, HIV drug effects, HIV Protease metabolism, HIV Protease Inhibitors chemistry, HIV Protease Inhibitors pharmacology, Indicators and Reagents, Kinetics, Molecular Structure, Structure-Activity Relationship, Urea chemistry, Urea pharmacology, Antiviral Agents chemical synthesis, HIV Protease Inhibitors chemical synthesis, Urea analogs & derivatives, Urea chemical synthesis
- Abstract
Two series of cyclic ureas modified at the P1/P1' residue were prepared and evaluated for HIV protease inhibition and whole cell antiviral activity. Compounds 8b, 10 (3- and 4-pyridylmethyl analogs) and 6b (4-methoxy analog) showed significant improvement in antiviral activity relative to lead compounds DMP323 and DMP 450.
- Published
- 1998
- Full Text
- View/download PDF
36. Population dynamics studies of wild-type and drug-resistant mutant HIV in mixed infections.
- Author
-
Rayner MM, Cordova B, and Jackson DA
- Subjects
- Alkynes, Benzoxazines, Cyclopropanes, Drug Resistance, Microbial, HIV genetics, HIV growth & development, HIV Infections drug therapy, Humans, Microbial Sensitivity Tests, Population Dynamics, Time Factors, Urea pharmacology, Viral Plaque Assay, Azepines pharmacology, HIV drug effects, HIV Infections virology, HIV Protease Inhibitors pharmacology, Oxazines pharmacology, Reverse Transcriptase Inhibitors pharmacology, Urea analogs & derivatives
- Abstract
We have studied the population dynamics in response to selective drug pressure of mixtures of wild-type and mutant HIV viruses exposed to either an inhibitor of the viral protease or a nonnucleoside allosteric inhibitor of the viral reverse transcriptase. In order to quantitate mutant virus present in a mixed population, we developed a selective plaque assay, which appears to be generally applicable to population dynamics studies where the viruses in question differ in the sensitivity to a given drug by at least 10-fold. In this assay system, the titer of virus in a mixture is measured in the absence and presence of a concentration of a specific inhibitor known to suppress virus replication by 99%. Virus detected in the presence of inhibitor corresponds to mutant virus, whereas detection in the absence of drug results in quantitation of the total virion population. Wild-type virus is then estimated by difference. Utilizing this system we studied the fate of mixtures of wild-type and the protease-resistant mutant variant I84V in the presence and absence of the cyclic urea HIV protease inhibitor, DMP 450. We also examined the dynamics of mixtures of wild-type and the resistant mutant variant, L100I, in the presence and absence of the drug DMP 266. In both systems we demonstrated that in the absence of drug, mutant virus is at a selective disadvantage for growth compared to wild-type, whereas in the presence of a specific inhibitor, mutant virus exhibits the selective growth advantage over wild-type virus. Better understanding of HIV population dynamics may allow the development of superior inhibitors and the careful application of combination therapy in the clinical setting., (Copyright 1997 Academic Press.)
- Published
- 1997
- Full Text
- View/download PDF
37. Design, synthesis, and evaluation of tetrahydropyrimidinones as an example of a general approach to nonpeptide HIV protease inhibitors.
- Author
-
De Lucca GV, Liang J, Aldrich PE, Calabrese J, Cordova B, Klabe RM, Rayner MM, and Chang CH
- Subjects
- Binding Sites, Computer Simulation, Crystallography, X-Ray, Cyclization, HIV Protease Inhibitors chemistry, HIV Protease Inhibitors pharmacology, Hydrogen Bonding, Models, Molecular, Molecular Conformation, Molecular Structure, Oximes chemistry, Oximes pharmacology, Pyrimidinones chemistry, Pyrimidinones pharmacology, Drug Design, HIV Protease Inhibitors chemical synthesis, Oximes chemical synthesis, Pyrimidinones chemical synthesis
- Abstract
Re-examination of the design of the cyclic urea class of HIV protease (HIVPR) inhibitors suggests a general approach to designing novel nonpeptide cyclic HIVPR inhibitors. This process involves the inversion of the stereochemical centers of the core transition-state isostere of the linear HIVPR inhibitors and cyclization of the resulting core using an appropriate cyclizing reagent. As an example, this process is applied to the diamino alcohol class of HIVPR inhibitors to give tetrahydropyrimidinones. Conformational analysis of the tetrahydropyrimidinones and modeling of its interaction with the active site of HIVPR suggested modifications which led to very potent inhibitors of HIVPR (24 with a Ki = 0.018 nM). The X-ray crystallographic structure of the complex of 24 with HIVPR confirms the analysis and modeling predictions. The example reported in this study and other examples that are cited indicate that this process may be generally applicable to other linear inhibitors.
- Published
- 1997
- Full Text
- View/download PDF
38. Improved P1/P1' substituents for cyclic urea based HIV-1 protease inhibitors: synthesis, structure-activity relationship, and X-ray crystal structure analysis.
- Author
-
Nugiel DA, Jacobs K, Cornelius L, Chang CH, Jadhav PK, Holler ER, Klabe RM, Bacheler LT, Cordova B, Garber S, Reid C, Logue KA, Gorey-Feret LJ, Lam GN, Erickson-Viitanen S, and Seitz SP
- Subjects
- Animals, Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacokinetics, Anti-HIV Agents pharmacology, Biological Availability, Cell Line, Crystallography, X-Ray, Dogs, HIV Protease Inhibitors chemical synthesis, HIV Protease Inhibitors pharmacokinetics, HIV Protease Inhibitors pharmacology, Humans, Magnetic Resonance Spectroscopy, Mass Spectrometry, Structure-Activity Relationship, HIV Protease Inhibitors chemistry, Urea analogs & derivatives
- Abstract
We present several novel P1/P1' substituents that can replace the characteristic benzyl P1/P1' moiety of the cyclic urea based HIV protease inhibitor series. These substituents typically provide 5-10-fold improvements in binding affinity compared to the unsubstituted benzyl analogs. The best substituent was the 3,4-(ethylenedioxy)benzyl group. Proper balancing of the molecule's lipophilicity facilitated the transfer of this improved binding affinity into a superior cellular antiviral activity profile. Several analogs were evaluated further for protein binding and resistance liabilities. Compound 18 (IC90 = 8.7 nM) was chosen for oral bioavailability studies based on its log P and solubility profile. A 10 mg/kg dose in dogs provided modest bioavailability with Cmax = 0.22 microg/mL. X-ray crystallographic analysis of two analogs revealed several interesting features responsible for the 3,4-(ethylenedioxy)benzyl-substituted analog's potency: (1) Comparing the two complexes revealed two distinct binding modes for each P1/P1' substituent; (2) The ethylenedioxy moieties are within 3.6 A of Pro 81 providing additional van der Waals contacts missing from the parent structure; (3) The enzyme's Arg 8 side chain moves away from the P1 substituent to accommodate the increased steric volume while maintaining a favorable hydrogen bond distance between the para oxygen substituent and the guanidine NH.
- Published
- 1997
- Full Text
- View/download PDF
39. Apoptosis mediated by HIV protease is preceded by cleavage of Bcl-2.
- Author
-
Strack PR, Frey MW, Rizzo CJ, Cordova B, George HJ, Meade R, Ho SP, Corman J, Tritch R, and Korant BD
- Subjects
- Animals, Base Sequence, Cells, Cultured, Electrophoresis, Polyacrylamide Gel, HIV Long Terminal Repeat, Humans, Lymphocytes metabolism, Mice, Molecular Sequence Data, NF-kappa B metabolism, Proto-Oncogene Proteins c-bcl-2, Tumor Necrosis Factor-alpha metabolism, Apoptosis, HIV Protease metabolism, Proto-Oncogene Proteins metabolism
- Abstract
Expression of the human immunodeficiency virus type 1 (HIV) protease in cultured cells leads to apoptosis, preceded by cleavage of bcl-2, a key negative regulator of cell death. In contrast, a high level of bcl-2 protects cells in vitro and in vivo from the viral protease and prevents cell death following HIV infection of human lymphocytes, while reducing the yields of viral structural proteins, infectivity, and tumor necrosis factor alpha. We present a model for HIV replication in which the viral protease depletes the infected cells of bcl-2, leading to oxidative stress-dependent activation of NF kappa B, a cellular factor required for HIV transcription, and ultimately to cell death. Purified bcl-2 is cleaved by HIV protease between phenylalanine 112 and alanine 113. The results suggest a new option for HIV gene therapy; bcl-2 muteins that have noncleavable alterations surrounding the HIV protease cleavage site.
- Published
- 1996
- Full Text
- View/download PDF
40. DMP 323, a nonpeptide cyclic urea inhibitor of human immunodeficiency virus (HIV) protease, specifically and persistently blocks intracellular processing of HIV gag polyprotein.
- Author
-
Rayner MM, Cordova BC, Meade RP, Aldrich PE, Jadhav PK, Ru Y, and Lam PY
- Subjects
- Azepines, Cells, Cultured, HIV-1 drug effects, HIV-1 ultrastructure, Humans, Microscopy, Electron, Protein Processing, Post-Translational drug effects, RNA, Viral metabolism, Urea pharmacology, Virus Replication drug effects, Gene Products, gag metabolism, HIV Protease Inhibitors pharmacology, HIV-1 enzymology, Urea analogs & derivatives
- Abstract
DMP 323, a C-2-symmetrical cyclic urea, is representative of a new class of inhibitors of human immunodeficiency virus protease. In this study, we correlate the potent antiviral activity of DMP 323 in acute infections with antiprotease activity assessed by monitoring the inhibition of the processing of viral gag precursor polyprotein from chronically infected lymphoid and monocytoid cell lines. Electron microscopic examination confirmed that the inhibition of gag processing was associated with the production of immature viral particles. Reduction of DMP 323 in the environment of unprocessed gag viral particles did not result in the resumption of gag processing for at least 72 h.
- Published
- 1994
- Full Text
- View/download PDF
41. IFN-induced 15-kDa protein is released from human lymphocytes and monocytes.
- Author
-
Knight E Jr and Cordova B
- Subjects
- Cell Communication, Cell Line, Humans, In Vitro Techniques, Molecular Weight, Precipitin Tests, Proteins chemistry, Time Factors, Interferon Type I pharmacology, Lymphocytes metabolism, Monocytes metabolism, Proteins metabolism
- Abstract
The enhancement or inhibition of synthesis of specific proteins by IFN is believed to cause subsequent IFN-induced biological responses. The roles of most of these proteins in the biological responses induced by the IFNs, for example, inhibition of virus replication and inhibition of cell growth, remain largely unknown. Our recent research has focused on the induction and synthesis of an IFN-induced 15-kDa protein. In this report we show that human lymphocytes and monocytes, after treatment with IFN-beta, release into the medium an IFN-induced 15-kDa protein. At 24 h after induction of the 15-kDa protein in lymphocytes or monocytes, more than 50% of the total 15-kDa protein is in the medium. The human monocytic cell line THP-1 also releases 15-kDa protein into the medium after its induction by IFN-beta. An intracellular half-life of 12 h has been calculated for the 15-kDa protein in monocytes and THP-1 cells. The exocellular release of the 15-kDa protein by lymphocytes and monocytes suggests that 1) it may have an intercellular signaling role and 2) it may be an in vivo mediator of some of the biological responses induced by IFN.
- Published
- 1991
42. A 15-kD interferon-induced protein and its 17-kD precursor: expression in Escherichia coli, purification, and characterization.
- Author
-
Feltham N, Hillman M Jr, Cordova B, Fahey D, Larsen B, Blomstrom D, and Knight E Jr
- Subjects
- Amino Acid Sequence, Bacterial Proteins isolation & purification, Crystallization, Escherichia coli drug effects, Escherichia coli genetics, Humans, Molecular Weight, Protein Precursors biosynthesis, Protein Precursors isolation & purification, Recombinant Proteins biosynthesis, Recombinant Proteins genetics, Bacterial Proteins biosynthesis, Escherichia coli metabolism, Interferons physiology
- Abstract
Using recombinant DNA technology, a 15-kD interferon (IFN)-induced protein and its 17-kD precursor have been expressed in Escherichia coli to obtain sufficient quantities of each protein for the investigation of their biological roles. Both the 15-kD and 17-kD proteins have been purified to homogeneity and crystallized. The recombinant 15-kD protein has an identical reversed-phase HPLC elution profile to that of the native 15-kD protein purified from human cells. Furthermore, the recombinant 15-kD and 17-kD proteins have identical amino- and carboxy-terminal amino acid sequences to those predicted from the DNA sequence. The native and recombinant 15-kD proteins give identical tryptic peptide maps, and the recombinant 17-kD protein gives only one additional tryptic peptide. We conclude that the recombinant 17-kD and 15-kD proteins are identical to the 17-kD precursor and the 15-kD stable product synthesized in human cells in response to IFN stimulation. In addition, we have demonstrated that the recombinant 17-kD precursor protein can be converted to the 15-kD protein by cytoplasmic extracts of human cells.
- Published
- 1989
- Full Text
- View/download PDF
43. A 15-kDa interferon-induced protein is derived by COOH-terminal processing of a 17-kDa precursor.
- Author
-
Knight E Jr, Fahey D, Cordova B, Hillman M, Kutny R, Reich N, and Blomstrom D
- Subjects
- Amino Acid Sequence, Cell Line, Cyanogen Bromide, Humans, Molecular Sequence Data, Molecular Weight, Neoplasm Proteins genetics, Proteins genetics, Interferon Type I pharmacology, Neoplasm Proteins biosynthesis, Protein Biosynthesis, Protein Processing, Post-Translational
- Abstract
An interferon-induced 15-kDa protein is synthesized from a precursor of higher molecular weight; the precursor contains 165 amino acids (17 kDa), whereas the stable product (15 kDa) contains 156 amino acids. The stable 15-kDa form is derived from the precursor 17-kDa form by the removal of eight amino acids from the COOH terminus and the methionine from the NH2 terminus. The existence of the precursor 17-kDa protein can be demonstrated after brief periods of in vivo labeling with [35S]methionine and by translation of mRNA in vitro.
- Published
- 1988
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