16 results on '"Orvieto F"'
Search Results
2. Discovery of MK-1462: GLP-1 and Glucagon Receptor Dual Agonist for the Treatment of Obesity and Diabetes.
- Author
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Palani A, Nawrocki AR, Orvieto F, Bianchi E, Mandić E, Pessi A, Huang C, Deng Q, Toussaint N, Walsh E, Reddy V, Ashley E, He H, Mumick S, Hawes B, Marsh D, Erion M, Nargund R, and Carrington PE
- Abstract
Peptide-based analogues of the gut-derived incretin hormone, glucagon-like peptide 1 (GLP1), stimulate insulin secretion in a glucose-dependent manner. Currently marketed GLP1 receptor (GLP1R) agonists are safe and effective in the management of Type 2 diabetes but often offer only modest weight loss. This has prompted the search for safe and effective alternatives to enhance the weight loss component of these treatments. We have demonstrated that concomitant activation GLP1R and the glucagon receptor (GCGR) can improve glucose metabolism and provide superior weight loss when compared to selective GLP1R agonism in preclinical species. This paper will highlight chemistry structure-activity relationship optimization and summarize in vivo efficacy studies toward the discovery of a once daily balanced dual agonist 12 (MK-1462), which was advanced into clinical trials., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)
- Published
- 2022
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3. Discovery of Insulin/GLP-1/Glucagon Triagonists for the Treatment of Diabetes and Obesity.
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Huang C, Palani A, Yang Z, Deng Q, Reddy V, Nargund RP, Lin S, Altezza S, Bianchi E, Orvieto F, and Carrington P
- Abstract
The combination of insulin and incretin-based therapies has emerged as a potential promising tactic for the treatment of diabetes. Here we report the first example of a unimolecular triagonist to simultaneously target insulin, GLP-1, and glucagon receptors, aiming for better glycemic control and superior weight loss. The strategy for constructing such a unimolecular triagonist is the conjugation of the insulin moiety and GLP-1R/GCGR coagonist peptide via alkyne-azide click chemistry. Two tractable series differentiated by insulin conjugation sites, B1
F and B29K , were identified. Triagonist 13 prepared through the conjugation at insulin B1F and position 24 of GLP-1R/GCGR coagonist exhibited insulin activity comparable to that of insulin degludec and potent and balanced GLP-1R and GCGR activities. Pharmacokinetic profiles of 13 in both rat and minipig were also discussed., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)- Published
- 2022
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4. Oligomerization, albumin binding and catabolism of therapeutic peptides in the subcutaneous compartment: An investigation on lipidated GLP-1 analogs.
- Author
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Gallo M, Vanni D, Esposito S, Alaimo N, Orvieto F, Rulli F, Missineo A, Caretti F, Bonelli F, Veneziano M, Orsatti L, and Monteagudo E
- Subjects
- Albumins, Animals, Half-Life, Hypoglycemic Agents, Liraglutide, Peptides, Rats, Diabetes Mellitus, Type 2, Glucagon-Like Peptide 1
- Abstract
Lipidation, a common strategy to improve half-life of therapeutic peptides, affects their tendency to oligomerize, their interaction with plasmatic proteins, and their catabolism. In this work, we have leveraged the use of NMR and SPR spectroscopy to elucidate oligomerization propensity and albumin interaction of different analogs of the two marketed lipidated GLP-1 agonists liraglutide and semaglutide. As most lipidated therapeutic peptides are administered by subcutaneous injection, we have also assessed in vitro their catabolism in the SC tissue using the LC-HRMS-based SCiMetPep assay. We observed that oligomerization had a shielding effect against catabolism. At the same time, binding to albumin may provide only limited protection from proteolysis due to the higher unbound peptide fraction present in the subcutaneous compartment with respect to the plasma. Finally, identification of catabolites in rat plasma after SC dosing of semaglutide showed a good correlation with the in vitro data, with Tyr
19 -Leu20 being the major cleavage site. Early characterization of the complex interplay between oligomerization, albumin binding, and catabolism at the injection site is essential for the synthesis of lipidated peptides with good pharmacokinetic profiles., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)- Published
- 2022
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5. Multiple Synthetic Routes to the Mini-Protein Omomyc and Coiled-Coil Domain Truncations.
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Brown ZZ, Mapelli C, Farasat I, Shoultz AV, Johnson SA, Orvieto F, Santoprete A, Bianchi E, McCracken AB, Chen K, Zhu X, Demma MJ, Lacey BM, Canada KA, Garbaccio RM, O'Neil J, and Walji A
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- Cell Line, Peptide Fragments, Protein Binding, DNA metabolism, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism
- Abstract
The Myc transcription factor represents an "undruggable" target of high biological interest due to its central role in various cancers. An abbreviated form of the c-Myc protein, called Omomyc, consists of the Myc DNA-binding domain and a coiled-coil region to facilitate dimerization of the 90 amino acid polypeptide. Here we present our results to evaluate the synthesis of Omomyc using three complementary strategies: linear Fmoc solid-phase peptide synthesis (SPPS) using several advancements for difficult sequences, native chemical ligation from smaller peptide fragments, and a high-throughput bacterial expression and assay platform for rapid mutagenesis. This multifaceted approach allowed access to up to gram quantities of the mini-protein and permitted in vitro and in vivo SAR exploration of this modality. DNA-binding results and cellular activity confirm that Omomyc and analogues presented here, are potent binders of the E-box DNA engaged by Myc for transcriptional activation and that this 90-amino acid mini-protein is cell permeable and can inhibit proliferation of Myc-dependent cell lines. We also present additional results on covalent homodimerization through disulfide formation of the full-length mini-protein and show the coiled-coil region can be truncated while preserving both DNA binding and cellular activity. Altogether, our results highlight the ability of advanced peptide synthesis to achieve SAR tractability in a challenging synthetic modality.
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- 2020
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6. Omomyc Reveals New Mechanisms To Inhibit the MYC Oncogene.
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Demma MJ, Mapelli C, Sun A, Bodea S, Ruprecht B, Javaid S, Wiswell D, Muise E, Chen S, Zelina J, Orvieto F, Santoprete A, Altezza S, Tucci F, Escandon E, Hall B, Ray K, Walji A, and O'Neil J
- Subjects
- Amino Acid Sequence, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Cell Line, Cell Line, Tumor, Chromatin Immunoprecipitation methods, DNA metabolism, DNA-Binding Proteins metabolism, Female, HCT116 Cells, Humans, Mice, Mice, Inbred BALB C, Peptide Fragments metabolism, Peptide Fragments pharmacology, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-myc antagonists & inhibitors, Proto-Oncogene Proteins c-myc pharmacology, Recombinant Proteins pharmacology, Transcription, Genetic, Transcriptional Activation, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Genes, myc, Peptide Fragments genetics, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism
- Abstract
The MYC oncogene is upregulated in human cancers by translocation, amplification, and mutation of cellular pathways that regulate Myc. Myc/Max heterodimers bind to E box sequences in the promoter regions of genes and activate transcription. The MYC inhibitor Omomyc can reduce the ability of MYC to bind specific box sequences in promoters of MYC target genes by binding directly to E box sequences as demonstrated by ch romatin i mmuno p recipitation (CHIP). Here, we demonstrate by both a p roximity l igation a ssay (PLA) and double chromatin immunoprecipitation (ReCHIP) that Omomyc preferentially binds to Max, not Myc, to mediate inhibition of MYC-mediated transcription by replacing MYC/MAX heterodimers with Omomyc/MAX heterodimers. The formation of Myc/Max and Omomyc/Max heterodimers occurs cotranslationally; Myc, Max, and Omomyc can interact with ribosomes and Max RNA under conditions in which ribosomes are intact. Taken together, our data suggest that the mechanism of action of Omomyc is to bind DNA as either a homodimer or a heterodimer with Max that is formed cotranslationally, revealing a novel mechanism to inhibit the MYC oncogene. We find that in vivo , Omomyc distributes quickly to kidneys and liver and has a short effective half-life in plasma, which could limit its use in vivo ., (Copyright © 2019 Demma et al.)
- Published
- 2019
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7. Polypharmacy through Phage Display: Selection of Glucagon and GLP-1 Receptor Co-agonists from a Phage-Displayed Peptide Library.
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Demartis A, Lahm A, Tomei L, Beghetto E, Di Biasio V, Orvieto F, Frattolillo F, Carrington PE, Mumick S, Hawes B, Bianchi E, Palani A, and Pessi A
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- Diabetes Mellitus drug therapy, Dipeptidyl Peptidase 4 metabolism, Humans, Obesity drug therapy, Peptide Library, Peptides genetics, Polypharmacy, Sequence Analysis, DNA, Glucagon-Like Peptide-1 Receptor agonists, Peptides chemical synthesis, Peptides pharmacology, Receptors, Glucagon agonists
- Abstract
A promising emerging area for the treatment of obesity and diabetes is combinatorial hormone therapy, where single-molecule peptides are rationally designed to integrate the complementary actions of multiple endogenous metabolically-related hormones. We describe here a proof-of-concept study on developing unimolecular polypharmacy agents through the use of selection methods based on phage-displayed peptide libraries (PDL). Co-agonists of the glucagon (GCG) and GLP-1 receptors were identified from a PDL sequentially selected on GCGR- and GLP1R-overexpressing cells. After two or three rounds of selection, 7.5% of randomly picked clones were GLP1R/GCGR co-agonists, and a further 1.53% were agonists of a single receptor. The phages were sequenced and 35 corresponding peptides were synthesized. 18 peptides were potent co-agonists, 8 of whom showed EC
50 ≤ 30 pM on each receptor, comparable to the best rationally designed co-agonists reported in the literature. Based on literature examples, two sequences were engineered to stabilize against dipeptidyl peptidase IV cleavage and prolong the in vivo half-life: the engineered peptides were comparably potent to the parent peptides on both receptors, highlighting the potential use of phage-derived peptides as therapeutic agents. The strategy described here appears of general value for the discovery of optimized polypharmacology paradigms across several metabolically-related hormones.- Published
- 2018
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8. Identification and SAR of novel pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1).
- Author
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Pescatore G, Branca D, Fiore F, Kinzel O, Bufi LL, Muraglia E, Orvieto F, Rowley M, Toniatti C, Torrisi C, and Jones P
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- Animals, BRCA1 Protein deficiency, BRCA1 Protein metabolism, Cell Line, Tumor, Crystallography, X-Ray, HeLa Cells, Humans, Indolizines chemistry, Indolizines metabolism, Microsomes, Liver drug effects, Microsomes, Liver enzymology, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerases metabolism, Protein Binding physiology, Rats, Structure-Activity Relationship, Poly(ADP-ribose) Polymerase Inhibitors, Pyrazines chemistry, Pyrazines metabolism
- Abstract
Herein we describe the discovery of a novel series of pyrrolo[1,2-a]pyrazin-1(2H)-one PARP inhibitors. Optimization led to compounds that display excellent PARP-1 enzyme potency and inhibit the proliferation of BRCA deficient cells in the low double-digit nanomolar range showing excellent selectivity over BRCA proficient cancer cells., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)
- Published
- 2010
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9. Identification of aminoethyl pyrrolo dihydroisoquinolinones as novel poly(ADP-ribose) polymerase-1 inhibitors.
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Branca D, Cerretani M, Jones P, Koch U, Orvieto F, Palumbi MC, Rowley M, Toniatti C, and Muraglia E
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- Antineoplastic Agents pharmacology, Binding Sites, Chemistry, Pharmaceutical methods, Crystallography, X-Ray methods, DNA Repair, Drug Design, Humans, Hydrogen Bonding, Inhibitory Concentration 50, Ligands, Models, Chemical, Polymers chemistry, Structure-Activity Relationship, Poly(ADP-ribose) Polymerase Inhibitors, Quinolones chemistry
- Abstract
PARP inhibitors have been demonstrated to retard intracellular DNA repair and therefore sensitize tumor cells to cytotoxic agents or ionizing radiation. We report the identification of a novel class of PARP1 inhibitors, containing a pyrrolo moiety fused to a dihydroisoquinolinone, derived from virtual screening of the proprietary collection. SAR exploration around the nitrogen of the aminoethyl appendage chain of 1 led to compounds that displayed low nanomolar activity in a PARP1 enzymatic assay.
- Published
- 2009
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10. Identification of substituted pyrazolo[1,5-a]quinazolin-5(4H)-one as potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors.
- Author
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Orvieto F, Branca D, Giomini C, Jones P, Koch U, Ontoria JM, Palumbi MC, Rowley M, Toniatti C, and Muraglia E
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- Amides chemistry, Chemistry, Organic methods, Chemistry, Pharmaceutical methods, Drug Design, Drug Evaluation, Preclinical, Enzyme Inhibitors pharmacology, HeLa Cells, Humans, Inhibitory Concentration 50, Models, Chemical, Molecular Structure, Pyrazoles pharmacology, Quinazolinones chemical synthesis, Quinazolinones pharmacology, Structure-Activity Relationship, Enzyme Inhibitors chemical synthesis, Poly(ADP-ribose) Polymerase Inhibitors, Pyrazoles chemical synthesis
- Abstract
A novel series of pyrazolo[1,5-a]quinazolin-5(4H)-one derivatives proved to be a potent class of PARP-1 inhibitors. An extensive SAR around the 3-position of pyrazole in the scaffold led to the discovery of amides derivatives as low nanomolar PARP-1 inhibitors.
- Published
- 2009
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11. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection.
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Summa V, Petrocchi A, Bonelli F, Crescenzi B, Donghi M, Ferrara M, Fiore F, Gardelli C, Gonzalez Paz O, Hazuda DJ, Jones P, Kinzel O, Laufer R, Monteagudo E, Muraglia E, Nizi E, Orvieto F, Pace P, Pescatore G, Scarpelli R, Stillmock K, Witmer MV, and Rowley M
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- Administration, Oral, Area Under Curve, Biological Availability, HIV Integrase Inhibitors administration & dosage, HIV Integrase Inhibitors pharmacokinetics, HIV Integrase Inhibitors therapeutic use, Half-Life, Humans, Magnetic Resonance Spectroscopy, Mass Spectrometry, Pyrrolidinones administration & dosage, Pyrrolidinones pharmacokinetics, Pyrrolidinones therapeutic use, Raltegravir Potassium, HIV Infections drug therapy, HIV Integrase Inhibitors pharmacology, Pyrrolidinones pharmacology
- Abstract
Human immunodeficiency virus type-1 (HIV-1) integrase is one of the three virally encoded enzymes required for replication and therefore a rational target for chemotherapeutic intervention in the treatment of HIV-1 infection. We report here the discovery of Raltegravir, the first HIV-integrase inhibitor approved by FDA for the treatment of HIV infection. It derives from the evolution of 5,6-dihydroxypyrimidine-4-carboxamides and N-methyl-4-hydroxypyrimidinone-carboxamides, which exhibited potent inhibition of the HIV-integrase catalyzed strand transfer process. Structural modifications on these molecules were made in order to maximize potency as HIV-integrase inhibitors against the wild type virus, a selection of mutants, and optimize the selectivity, pharmacokinetic, and metabolic profiles in preclinical species. The good profile of Raltegravir has enabled its progression toward the end of phase III clinical trials for the treatment of HIV-1 infection and culminated with the FDA approval as the first HIV-integrase inhibitor for the treatment of HIV-1 infection.
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- 2008
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12. Design and synthesis of bicyclic pyrimidinones as potent and orally bioavailable HIV-1 integrase inhibitors.
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Muraglia E, Kinzel O, Gardelli C, Crescenzi B, Donghi M, Ferrara M, Nizi E, Orvieto F, Pescatore G, Laufer R, Gonzalez-Paz O, Di Marco A, Fiore F, Monteagudo E, Fonsi M, Felock PJ, Rowley M, and Summa V
- Subjects
- Administration, Oral, Aminopyridines pharmacokinetics, Aminopyridines pharmacology, Animals, Azepines pharmacokinetics, Azepines pharmacology, Biological Availability, Bridged Bicyclo Compounds, Heterocyclic pharmacokinetics, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Cell Line, Dogs, HIV Integrase genetics, HIV Integrase Inhibitors pharmacokinetics, HIV Integrase Inhibitors pharmacology, HIV-1 drug effects, Humans, Macaca mulatta, Microsomes, Liver metabolism, Pyrimidinones pharmacokinetics, Pyrimidinones pharmacology, Rats, Stereoisomerism, Structure-Activity Relationship, Aminopyridines chemical synthesis, Azepines chemical synthesis, Bridged Bicyclo Compounds, Heterocyclic chemical synthesis, HIV Integrase metabolism, HIV Integrase Inhibitors chemical synthesis, Pyrimidinones chemical synthesis
- Abstract
HIV integrase is one of the three enzymes encoded by HIV genome and is essential for viral replication, but integrase inhibitors as marketed drugs have just very recently started to emerge. In this study, we show the evolution from the N-methylpyrimidinone structure to bicyclic pyrimidinones. Introduction of a suitably substituted amino moiety modulated the physical-chemical properties of the molecules and conferred nanomolar activity in the inhibition of spread of HIV-1 infection in cell culture. An extensive SAR study led to sulfamide (R)- 22b, which inhibited the strand transfer with an IC50 of 7 nM and HIV infection in MT4 cells with a CIC95 of 44 nM, and ketoamide (S)- 28c that inhibited strand transfer with an IC50 of 12 nM and the HIV infection in MT4 cells with a CIC95 of 13 nM and exhibited a good pharmacokinetic profile when dosed orally to preclinical species.
- Published
- 2008
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13. Discovery and synthesis of HIV integrase inhibitors: development of potent and orally bioavailable N-methyl pyrimidones.
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Gardelli C, Nizi E, Muraglia E, Crescenzi B, Ferrara M, Orvieto F, Pace P, Pescatore G, Poma M, Ferreira Mdel R, Scarpelli R, Homnick CF, Ikemoto N, Alfieri A, Verdirame M, Bonelli F, Paz OG, Taliani M, Monteagudo E, Pesci S, Laufer R, Felock P, Stillmock KA, Hazuda D, Rowley M, and Summa V
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- Administration, Oral, Animals, Biological Availability, Blood Proteins metabolism, Cell Line, Tumor, Dogs, HIV Integrase Inhibitors pharmacokinetics, HIV Integrase Inhibitors pharmacology, HIV-1 enzymology, HIV-1 physiology, Humans, Macaca mulatta, Morpholines pharmacokinetics, Morpholines pharmacology, Protein Binding, Pyrimidinones pharmacokinetics, Pyrimidinones pharmacology, Rats, Stereoisomerism, Structure-Activity Relationship, Virus Replication drug effects, HIV Integrase chemistry, HIV Integrase Inhibitors chemical synthesis, HIV-1 drug effects, Morpholines chemical synthesis, Pyrimidinones chemical synthesis
- Abstract
The human immunodeficiency virus type-1 (HIV-1) encodes three enzymes essential for viral replication: a reverse transcriptase, a protease, and an integrase. The latter is responsible for the integration of the viral genome into the human genome and, therefore, represents an attractive target for chemotherapeutic intervention against AIDS. A drug based on this mechanism has not yet been approved. Benzyl-dihydroxypyrimidine-carboxamides were discovered in our laboratories as a novel and metabolically stable class of agents that exhibits potent inhibition of the HIV integrase strand transfer step. Further efforts led to very potent compounds based on the structurally related N-Me pyrimidone scaffold. One of the more interesting compounds in this series is the 2-N-Me-morpholino derivative 27a, which shows a CIC95 of 65 nM in the cell in the presence of serum. The compound has favorable pharmacokinetic properties in three preclinical species and shows no liabilities in several counterscreening assays.
- Published
- 2007
- Full Text
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14. Dihydroxypyrimidine-4-carboxamides as novel potent and selective HIV integrase inhibitors.
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Pace P, Di Francesco ME, Gardelli C, Harper S, Muraglia E, Nizi E, Orvieto F, Petrocchi A, Poma M, Rowley M, Scarpelli R, Laufer R, Gonzalez Paz O, Monteagudo E, Bonelli F, Hazuda D, Stillmock KA, and Summa V
- Subjects
- Animals, Biological Availability, Blood Proteins metabolism, Cell Line, Tumor, Dogs, HIV Integrase Inhibitors pharmacokinetics, HIV Integrase Inhibitors pharmacology, Half-Life, Humans, Macaca mulatta, Protein Binding, Pyridines chemistry, Pyridines pharmacology, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Rats, Structure-Activity Relationship, Virus Replication, HIV Integrase Inhibitors chemical synthesis, HIV-1 drug effects, Pyridines chemical synthesis, Pyrimidines chemical synthesis
- Abstract
Human immunodeficiency virus type-1 (HIV-1) integrase, one of the three constitutive viral enzymes required for replication, is a rational target for chemotherapeutic intervention in the treatment of AIDS that has also recently been confirmed in the clinical setting. We report here on the design and synthesis of N-benzyl-5,6-dihydroxypyrimidine-4-carboxamides as a class of agents which exhibits potent inhibition of the HIV-integrase-catalyzed strand transfer process. In the current study, structural modifications on these molecules were made in order to examine effects on HIV-integrase inhibitory potencies. One of the most interesting compounds for this series is 2-[1-(dimethylamino)-1-methylethyl]-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide 38, with a CIC95 of 78 nM in the cell-based assay in the presence of serum proteins. The compound has favorable pharmacokinetic properties in preclinical species (rats, dogs, and monkeys) and shows no liabilities in several counterscreening assays, highlighting its potential as a clinically useful antiviral agent.
- Published
- 2007
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15. Tetrazole thioacetanilides: potent non-nucleoside inhibitors of WT HIV reverse transcriptase and its K103N mutant.
- Author
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Muraglia E, Kinzel OD, Laufer R, Miller MD, Moyer G, Munshi V, Orvieto F, Palumbi MC, Pescatore G, Rowley M, Williams PD, and Summa V
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- Acetanilides chemistry, Animals, HIV-1 enzymology, HIV-1 genetics, Rats, Reverse Transcriptase Inhibitors chemistry, Structure-Activity Relationship, Acetanilides pharmacology, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, Mutation, Reverse Transcriptase Inhibitors pharmacology
- Abstract
A series of aryltetrazolylacetanilides was synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors on wild-type virus and on the clinically relevant K103N mutant strain. Extensive SAR investigation led to potent compounds, with nanomolar activity on K103N, and orally bioavailable in rats.
- Published
- 2006
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16. Novel, potent phenethylamide inhibitors of the hepatitis C virus (HCV) NS3 protease: probing the role of P2 aryloxyprolines with hybrid structures.
- Author
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Orvieto F, Koch U, Matassa VG, and Muraglia E
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- Aminobutyrates chemistry, Aniline Compounds pharmacology, Antiviral Agents pharmacology, Hepacivirus drug effects, Hepacivirus genetics, Hydroquinones chemistry, Hydroxyproline chemistry, Models, Molecular, Oligopeptides pharmacology, Protease Inhibitors pharmacology, RNA Helicases, Serine Endopeptidases, Stereoisomerism, Structure-Activity Relationship, Viral Nonstructural Proteins, Aniline Compounds chemical synthesis, Antiviral Agents chemical synthesis, Hepacivirus metabolism, Oligopeptides chemical synthesis, Protease Inhibitors chemical synthesis
- Abstract
Synthesis of hybrid HCV NS3 protease/NS4A inhibitors having the 4,4-difluoroaminobutyric acid (difluoroAbu) phenethylamides as P1-P1' and quinolyloxyprolines as P2 fragments led to 7 (IC(50) 54 nM). Molecular modelling suggests that this potent tripeptide inhibitor utilizes interactions in the S1', S1, S2, S3 and S4 sites of the protease.
- Published
- 2003
- Full Text
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