19 results on '"Lanza TJ"'
Search Results
2. The design and synthesis of potent, selective benzodiazepine sulfonamide bombesin receptor subtype 3 (BRS-3) agonists with an increased barrier of atropisomerization.
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Chobanian HR, Guo Y, Liu P, Lanza TJ Jr, Chioda M, Chang L, Kelly TM, Kan Y, Palyha O, Guan XM, Marsh DJ, Metzger JM, Raustad K, Wang SP, Strack AM, Gorski JN, Miller R, Pang J, Lyons K, Dragovic J, Ning JG, Schafer WA, Welch CJ, Gong X, Gao YD, Hornak V, Reitman ML, Nargund RP, and Lin LS
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- Animals, Humans, Mice, Protein Binding, Rats, Receptors, Bombesin metabolism, Stereoisomerism, Sulfonamides pharmacokinetics, Temperature, Benzodiazepines chemistry, Drug Design, Receptors, Bombesin agonists, Sulfonamides chemical synthesis, Sulfonamides chemistry
- Abstract
Bombesin receptor subtype 3 (BRS-3) is an orphan G-protein coupled receptor expressed primarily in the hypothalamus which plays a role in the onset of both diabetes and obesity. We report herein our progress made towards identifying a potent, selective bombesin receptor subtype-3 (BRS-3) agonist related to the previously described MK-7725(1) Chobanian et al. (2012) that would prevent atropisomerization through the increase of steric bulk at the C-2 position. This would thereby make clinical development of this class of compounds more cost effective by inhibiting racemization which can occur over long periods of time at room/elevated temperature., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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3. Discovery of MK-7725, A Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity.
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Chobanian HR, Guo Y, Liu P, Chioda M, Lanza TJ Jr, Chang L, Kelly TM, Kan Y, Palyha O, Guan XM, Marsh DJ, Metzger JM, Gorski JN, Raustad K, Wang SP, Strack AM, Miller R, Pang J, Madeira M, Lyons K, Dragovic J, Reitman ML, Nargund RP, and Lin LS
- Abstract
Extensive structure-activity relationship studies of a series derived from atropisomer 1, a previously described chiral benzodiazepine sulfonamide series, led to a potent, brain penetrant and selective compound with excellent preclinical pharmacokinetic across species. We also describe the utilization of a high throughput mouse pharmacodynamic assay which allowed for expedient assessment of pharmacokinetic and brain distribution.
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- 2012
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4. Discovery of benzodiazepine sulfonamide-based bombesin receptor subtype 3 agonists and their unusual chirality.
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Liu P, Lanza TJ Jr, Chioda M, Jones C, Chobanian HR, Guo Y, Chang L, Kelly TM, Kan Y, Palyha O, Guan XM, Marsh DJ, Metzger JM, Ramsay K, Wang SP, Strack AM, Miller R, Pang J, Lyons K, Dragovic J, Ning JG, Schafer WA, Welch CJ, Gong X, Gao YD, Hornak V, Ball RG, Tsou N, Reitman ML, Wyvratt MJ, Nargund RP, and Lin LS
- Abstract
We report herein the discovery of benzodiazepine sulfonamide-based bombesin receptor subtype 3 (BRS-3) agonists and their unusual chirality. Starting from a high-throughput screening lead, we prepared a series of BRS-3 agonists with improved potency and pharmacokinetic properties, of which compound 8a caused mechanism-based, dose-dependent food intake reduction and body weight loss after oral dosing in diet-induced obese mice. This effort also led to the discovery of a novel family of chiral molecules originated from the conformationally constrained seven-membered diazepine ring.
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- 2011
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5. In vitro and in vivo metabolism of a novel cannabinoid-1 receptor inverse agonist, taranabant, in rats and monkeys.
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Reddy VB, Doss GA, Karanam BV, Samuel K, Lanza TJ Jr, Lin LS, Yu NX, Zhang AS, Raab CE, Stearns RA, and Kumar S
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- Amides blood, Amides chemistry, Amides pharmacokinetics, Animals, Antibodies, Monoclonal pharmacology, Body Fluids metabolism, Brain drug effects, Brain metabolism, Female, Haplorhini, Humans, Ketoconazole pharmacology, Magnetic Resonance Spectroscopy, Male, Mass Spectrometry, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Pyridines blood, Pyridines chemistry, Pyridines pharmacokinetics, Radioactivity, Rats, Amides metabolism, Drug Inverse Agonism, Pyridines metabolism, Receptor, Cannabinoid, CB1 agonists, Receptor, Cannabinoid, CB1 antagonists & inhibitors
- Abstract
The metabolism and excretion of taranabant (MK-0364, N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2{[5-(trifluoromethyl)pyridine-2-yl]oxy}propanamide), a potent cannabinoid-1 receptor inverse agonist, were evaluated in rats and rhesus monkeys. Following administration of [¹⁴C]taranabant, the majority of the radioactivity was excreted within 72 h. In both rats and rhesus monkeys, taranabant was eliminated primarily via oxidative metabolism, followed by excretion of metabolites into bile. Major pathways of metabolism that were common to rats and rhesus monkeys included hydroxylation at the benzylic carbon adjacent to the cyanophenyl ring to form a biologically active circulating metabolite M1, and oxidation of one of the two geminal methyl groups of taranabant or M1 to the corresponding diastereomeric carboxylic acids. Oxidation of the cyanophenyl ring, followed by conjugation with glutathione or glucuronic acid, was a major pathway of metabolism only in the rat and was not detected in the rhesus monkey. Metabolism profiles of taranabant in liver microsomes in vitro were qualitatively similar in rats, rhesus monkeys and humans and included formation of M1 and oxidation of taranabant or M1 to the corresponding carboxylic acids via oxidation of a geminal methyl group. In human liver microsomes, metabolism of taranabant was mediated primarily by CYP3A4.
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- 2010
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6. Synthesis and cannabinoid-1 receptor binding affinity of conformationally constrained analogs of taranabant.
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Kopka IE, Lin LS, Jewell JP, Lanza TJ, Fong TM, Shen CP, Lao ZJ, Ha S, Castonguay LG, Van der Ploeg L, Goulet MT, and Hagmann WK
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- Amides chemical synthesis, Amides pharmacology, Anti-Obesity Agents chemistry, Anti-Obesity Agents pharmacology, Computer Simulation, Humans, Models, Molecular, Molecular Conformation, Protein Binding, Pyridines chemical synthesis, Pyridines pharmacology, Receptor, Cannabinoid, CB1 metabolism, Amides chemistry, Anti-Obesity Agents chemical synthesis, Pyridines chemistry, Receptor, Cannabinoid, CB1 chemistry
- Abstract
The design, synthesis, and binding activity of ring constrained analogs of the acyclic cannabinoid-1 receptor (CB1R) inverse agonist taranabant 1 are described. The initial inspiration for these taranabant derivatives was its conformation 1a, determined by (1)H NMR, X-ray, and molecular modeling. The constrained analogs were all much less potent than their acyclic parent structure. The results obtained are discussed in the context of a predicted binding of 1 to a homology model of CB1R., (2010 Elsevier Ltd. All rights reserved.)
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- 2010
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7. Importance of mechanistic drug metabolism studies in support of drug discovery: A case study with an N -sulfonylated dipeptide VLA-4 antagonist in rats.
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Tang W, Stearns RA, Chen Q, Bleasby K, Teffera Y, Colletti A, Hafey M, Evers R, Dean DC, Magriotis PA, Lanza TJ, Lin LS, Hagmann WK, and Baillie TA
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- Animals, Cells, Cultured, Cyclosporine metabolism, Dogs, Inactivation, Metabolic, Microsomes, Liver metabolism, Organic Anion Transporters, Sodium-Independent metabolism, Phenylalanine metabolism, Phenylalanine physiology, Rats, Rats, Sprague-Dawley, Solute Carrier Organic Anion Transporter Family Member 1B3, Time Factors, Triazoles pharmacology, Integrin alpha4beta1 antagonists & inhibitors, Phenylalanine analogs & derivatives
- Abstract
N-(1-(3,5-dichlorobenzenesulfonyl)-2S-methyl-azetidine-2-carbonyl)-L-4-(2',6'-dimethoxyphenyl)phenylalanine (1) is a potent antagonist of the very late activating (VLA) antigen-4. During initial screening, 1 exhibited an apparent plasma clearance (CL) of 227 ml min(-1) kg(-1) in Sprague-Dawley rats following an intravenous bolus dose formulated in an aqueous solution containing 40% polyethylene glycol. Such a high CL value led to speculation that the elimination of compound 1 involved extra-hepatic tissues. However, the apparent plasma CL was reduced to 97 ml in(-1) kg(-1) when a 2-min time point was added to sample collections, and further decreased to 48 ml min(-1) kg(-1) after the dose was formulated in rat plasma. The lung extraction of 1 in rats was negligible whereas the hepatic extraction was > or =90%, based on comparison of area under the curve (AUC) values derived from intra-artery, intravenous, and portal vein administration. In rats dosed intravenously with [(14)C]-1, approximately 91% of the radioactivity was recovered in bile over 48 h, with 85% accounted for in the first 4-h samples. The biliary radioactivity profile consisted of approximately 30% intact parent compound, 20% 1-glucuronide, and 50% oxidation products resulting from O-demethylation or hydroxylation reactions. When incubated with rat liver microsomes, oxidative metabolism of 1 was inhibited completely by 1-aminobenzotriazole (ABT), whereas the oxidation and glucuronidation reactions were little affected in the presence of cyclosporin A (CsA). In contrast, the hepatic extraction of 1 in rats was unperturbed in animals pre-dosed with ABT, but was reduced approximately 60% following treatment with CsA. In vitro, 1 was a substrate of the rat organic anion transporter Oatp1b2, and its cellular uptake was inhibited by CsA. In addition, the hepatic extraction of 1 was approximately 30% lower in Eisai hyperbilirubinaemic rats which lack functional multidrug resistant protein-2 (MRP2). Collectively, these data suggest that the clearance of 1 in rats likely is a result of the combined processes of hepatic oxidation, glucuronidation and biliary excretion, all of which are facilitated by active hepatic uptake of parent compound and subsequent active efflux of both unchanged parent and its metabolites into bile. It was concluded, therefore, that multiple mechanisms contribute to the clearance of 1 in rats, and suggest that appropriate pharmacokinetic properties might be difficult to achieve for this class of compounds. This case study demonstrates that an integrated strategy, incorporating both rapid screening and mechanistic investigations, is of particular value in supporting drug discovery efforts and decision-making processes.
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- 2008
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8. Discovery of N-{(1S,2S)-2-(3-cyanophenyl)- 3-[4-(2-[18F]fluoroethoxy)phenyl]-1-methylpropyl}- 2-methyl-2-[(5-methylpyridin-2-yl)oxy]propanamide, a cannabinoid-1 receptor positron emission tomography tracer suitable for clinical use.
- Author
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Liu P, Lin LS, Hamill TG, Jewell JP, Lanza TJ Jr, Gibson RE, Krause SM, Ryan C, Eng W, Sanabria S, Tong X, Wang J, Levorse DA, Owens KA, Fong TM, Shen CP, Lao J, Kumar S, Yin W, Payack JF, Springfield SA, Hargreaves R, Burns HD, Goulet MT, and Hagmann WK
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- Amides chemistry, Amides pharmacokinetics, Animals, Brain diagnostic imaging, Brain metabolism, CHO Cells, Cricetinae, Cricetulus, Humans, Macaca mulatta, Positron-Emission Tomography, Pyridines chemistry, Pyridines pharmacokinetics, Radioligand Assay, Radiopharmaceuticals chemistry, Radiopharmaceuticals pharmacokinetics, Receptor, Cannabinoid, CB1 agonists, Receptor, Cannabinoid, CB1 antagonists & inhibitors, Recombinant Proteins metabolism, Structure-Activity Relationship, Amides chemical synthesis, Fluorine Radioisotopes, Pyridines chemical synthesis, Radiopharmaceuticals chemical synthesis, Receptor, Cannabinoid, CB1 metabolism
- Abstract
The discovery of a structurally distinct cannabinoid-1 receptor (CB1R) positron emission tomography tracer is described. Starting from an acyclic amide CB1R inverse agonist (1) as the lead compound, an efficient route to introduce 18F to the molecule was developed. Further optimization focused on reducing the lipophilicity and increasing the CB1R affinity. These efforts led to the identification of [18F]-16 that exhibited good brain uptake and an excellent signal-to-noise ratio in rhesus monkeys.
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- 2007
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9. Antiobesity efficacy of a novel cannabinoid-1 receptor inverse agonist, N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), in rodents.
- Author
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Fong TM, Guan XM, Marsh DJ, Shen CP, Stribling DS, Rosko KM, Lao J, Yu H, Feng Y, Xiao JC, Van der Ploeg LH, Goulet MT, Hagmann WK, Lin LS, Lanza TJ Jr, Jewell JP, Liu P, Shah SK, Qi H, Tong X, Wang J, Xu SS, Francis B, Strack AM, MacIntyre DE, and Shearman LP
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- Amides chemistry, Amides metabolism, Animals, Anti-Obesity Agents chemistry, Anti-Obesity Agents metabolism, Binding, Competitive drug effects, Body Temperature drug effects, Body Weight drug effects, CHO Cells, Colforsin pharmacology, Cricetinae, Cricetulus, Cyclic AMP metabolism, Cyclohexanols pharmacology, Dose-Response Relationship, Drug, Eating drug effects, Humans, Indoles metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Structure, Obesity metabolism, Obesity physiopathology, Piperidines metabolism, Pyridines chemistry, Pyridines metabolism, Rats, Rats, Sprague-Dawley, Receptor, Cannabinoid, CB1 genetics, Receptor, Cannabinoid, CB1 physiology, Transfection, Amides pharmacology, Anti-Obesity Agents pharmacology, Obesity drug therapy, Pyridines pharmacology, Receptor, Cannabinoid, CB1 metabolism
- Abstract
The cannabinoid-1 receptor (CB1R) has been implicated in the control of energy balance. To explore the pharmacological utility of CB1R inhibition for the treatment of obesity, we evaluated the efficacy of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364) and determined the relationship between efficacy and brain CB1R occupancy in rodents. MK-0364 was shown to be a highly potent CB1R inverse agonist that inhibited the binding and functional activity of various agonists with a binding K(i) of 0.13 nM for the human CB1R in vitro. MK-0364 dose-dependently inhibited food intake and weight gain, with an acute minimum effective dose of 1 mg/kg in diet-induced obese (DIO) rats. CB1R mechanism-based effect was demonstrated for MK-0364 by its lack of efficacy in CB1R-deficient mice. Chronic treatment of DIO rats with MK-0364 dose-dependently led to significant weight loss with a minimum effective dose of 0.3 mg/kg (p.o.), or a plasma C(max) of 87 nM. Weight loss was accompanied by the loss of fat mass. Partial occupancy (30-40%) of brain CB1R by MK-0364 was sufficient to reduce body weight. The magnitude of weight loss was correlated with brain CB1R occupancy. The partial receptor occupancy requirement for efficacy was also consistent with the reduced food intake of the heterozygous mice carrying one disrupted allele of CB1R gene compared with the wild-type mice. These studies demonstrated that MK-0364 is a highly potent and selective CB1R inverse agonist and that it is orally active in rodent models of obesity.
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- 2007
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10. Substituted acyclic sulfonamides as human cannabinoid-1 receptor inverse agonists.
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Armstrong HE, Galka A, Lin LS, Lanza TJ Jr, Jewell JP, Shah SK, Guthikonda R, Truong Q, Chang LL, Quaker G, Colandrea VJ, Tong X, Wang J, Xu S, Fong TM, Shen CP, Lao J, Chen J, Shearman LP, Stribling DS, Rosko K, Strack A, Ha S, Van der Ploeg L, Goulet MT, and Hagmann WK
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- Animals, Anti-Obesity Agents chemical synthesis, Anti-Obesity Agents pharmacology, Brain Chemistry, Cannabinoid Receptor Modulators pharmacology, Humans, Hypothermia drug therapy, Inhibitory Concentration 50, Pharmacokinetics, Rats, Receptor, Cannabinoid, CB1 agonists, Structure-Activity Relationship, Sulfonamides pharmacology, Cannabinoid Receptor Modulators chemical synthesis, Receptor, Cannabinoid, CB1 drug effects, Sulfonamides chemical synthesis
- Abstract
Sulfonamide analogues of the potent CB1R inverse agonist taranabant were prepared and optimized for potency and selectivity for CB1R. They were variably more potent than the corresponding amide analogues. The most potent representative 22 had good pharmacokinetic and brain levels, but was modestly active in blocking CB1R agonist-mediated hypothermia.
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- 2007
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11. Discovery of N-[(1S,2S)-3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2- {[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity.
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Lin LS, Lanza TJ Jr, Jewell JP, Liu P, Shah SK, Qi H, Tong X, Wang J, Xu SS, Fong TM, Shen CP, Lao J, Xiao JC, Shearman LP, Stribling DS, Rosko K, Strack A, Marsh DJ, Feng Y, Kumar S, Samuel K, Yin W, Van der Ploeg LH, Goulet MT, and Hagmann WK
- Subjects
- Animals, Anti-Obesity Agents chemical synthesis, Anti-Obesity Agents chemistry, Body Weight drug effects, Cannabinoids chemical synthesis, Cannabinoids chemistry, Cyclic AMP metabolism, Eating drug effects, Humans, Liver drug effects, Liver metabolism, Microsomes drug effects, Microsomes metabolism, Rats, Receptor, Cannabinoid, CB1 antagonists & inhibitors, Receptor, Cannabinoid, CB1 metabolism, Receptor, Cannabinoid, CB2 antagonists & inhibitors, Receptor, Cannabinoid, CB2 metabolism, Anti-Obesity Agents pharmacology, Cannabinoids pharmacology, Obesity drug therapy, Receptor, Cannabinoid, CB1 agonists, Receptor, Cannabinoid, CB2 agonists
- Abstract
The discovery of novel acyclic amide cannabinoid-1 receptor inverse agonists is described. They are potent, selective, orally bioavailable, and active in rodent models of food intake and body weight reduction. A major focus of the optimization process was to increase in vivo efficacy and to reduce the potential for formation of reactive metabolites. These efforts led to the identification of compound 48 for development as a clinical candidate for the treatment of obesity.
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- 2006
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12. Effects of mutations at conserved TM II residues on ligand binding and activation of mouse 5-HT6 receptor.
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Zhang J, Shen CP, Xiao JC, Lanza TJ, Lin LS, Francis BE, Fong TM, and Chen RZ
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- Amino Acid Sequence, Amino Acid Substitution, Animals, Cell Line, Cyclic AMP metabolism, Humans, Ligands, Mice, Molecular Sequence Data, Mutagenesis, Site-Directed, Piperazines metabolism, Protein Structure, Tertiary, Receptors, Serotonin chemistry, Receptors, Serotonin genetics, Serotonin metabolism, Serotonin Antagonists metabolism, Serotonin Receptor Agonists metabolism, Sulfonamides metabolism, Transfection, Receptors, Serotonin metabolism
- Abstract
An aspartate residue (Asp-72) in the transmembrane helix II of mouse 5-hydroxytryptamine-6 receptor (5-HT6) is conserved among most G protein-coupled receptors. We have examined the functional significance of this residue by site-directed mutagenesis. A single Asp --> Ala (D72A) mutation resulted in an 8-fold decrease in apparent affinity for 5-HT, and a 60-fold reduction in EC50 value of agonist-induced stimulation of adenylyl cyclase. A F69L/T70I/D72A triple mutant showed a 2-fold reduction in apparent affinity for 5-HT but complete loss of adenylyl cyclase stimulation. Binding of SB-258585 (4-iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzene-sulfonamide), a selective 5-HT6 antagonist, was mildly affected (2- to 4-fold decrease in affinity) in the two mutants. Our data suggest that Asp-72 and additional residues toward the intracellular side of TM II have a limited role in ligand binding but are critical for functional activation of the 5-HT6 receptor.
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- 2006
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13. Bioisosteric replacement of anilide with benzoxazole: potent and orally bioavailable antagonists of VLA-4.
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Lin LS, Lanza TJ Jr, Castonguay LA, Kamenecka T, McCauley E, Van Riper G, Egger LA, Mumford RA, Tong X, MacCoss M, Schmidt JA, and Hagmann WK
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- Animals, Biological Availability, Hydrogen Bonding, Rats, Anilides chemistry, Benzoxazoles chemistry, Integrin alpha4beta1 antagonists & inhibitors
- Abstract
We have designed and synthesized a series of heterocyclic bioisosteres for an anilide based on molecular modeling. Excellent potency was retained in the benzoxazole and the benzimidazole derivatives, where a hydrogen bond acceptor is appropriately positioned to mimic the amide bond oxygen. The deletion of the hydrogen bond donor (N-H) led to improved lipophilicity and bioavailability. In the process, 9a was identified as a potent, specific, and bioavailable VLA-4 antagonist, while 9c was found to be a potent and bioavailable dual antagonist of VLA-4 and alpha(4)beta(7).
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- 2004
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14. A small molecule alpha4beta1/alpha4beta7 antagonist differentiates between the low-affinity states of alpha4beta1 and alpha4beta7: characterization of divalent cation dependence.
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Egger LA, Cao J, McCallum C, Kidambi U, Van Riper G, McCauley E, Mumford RA, Lanza TJ, Lin LS, de Laszlo SE, Young DN, Yang G, Dean DC, Raab CE, Wallace MA, Jones AN, Hagmann WK, Schmidt JA, Pepinsky RB, Scott DM, Lee WC, Cornebise MA, and Detmers PA
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- Binding Sites, Cell Line, Dipeptides chemistry, Humans, Integrin alpha4beta1 metabolism, Integrins metabolism, Jurkat Cells, K562 Cells, Kinetics, Ligands, Phenylalanine analogs & derivatives, Phenylalanine chemistry, Phenylurea Compounds chemistry, Protein Binding, Radioligand Assay, Sulfur Radioisotopes, Tumor Cells, Cultured, Vascular Cell Adhesion Molecule-1 metabolism, Cations, Divalent metabolism, Dipeptides pharmacology, Integrin alpha4beta1 antagonists & inhibitors, Integrins antagonists & inhibitors, Phenylalanine pharmacology, Phenylurea Compounds pharmacology
- Abstract
An alpha4beta1/alpha4beta7 dual antagonist, 35S-compound 1, was used as a model ligand to study the effect of divalent cations on the activation state and ligand binding properties of alpha4 integrins. In the presence of 1 mM each Ca2+/Mg2+, 35S-compound 1 bound to several cell lines expressing both alpha4beta1 and alpha4beta7, but 2S-[(1-benzenesulfonyl-pyrrolidine-2S-carbonyl)-amino]-4-[4-methyl-2S-(methyl-[2-[4-(3-o-tolyl-ureido)-phenyl]-acetyl]-amino) pentanoylamino]-butyric acid (BIO7662), a specific alpha4beta1 antagonist, completely inhibited 35S-compound 1 binding, suggesting that alpha4beta1 was responsible for the observed binding. 35S-Compound 1 bound RPMI-8866 cells expressing predominantly alpha4beta7 with a KD of 1.9 nM in the presence of 1 mM Mn2+, and binding was inhibited only 29% by BIO7662, suggesting that the probe is a potent antagonist of activated alpha4beta7. With Ca2+/Mg2+, 35S-compound 1 bound Jurkat cells expressing primarily alpha4beta1 with a KD of 18 nM. In contrast, the binding of 35S-compound 1 to Mn2+-activated Jurkat cells occurred slowly, reaching equilibrium by 60 min, and failed to dissociate within another 60 min. The ability of four alpha4beta1/alpha4beta7 antagonists to block binding of activated alpha4beta1 or alpha4beta7 to vascular cell adhesion molecule-1 or mucosal addressin cell adhesion molecule-1, respectively, or to 35S-compound 1 was measured, and a similar rank order of potency was observed for native ligand and probe. Inhibition of 35S-compound 1 binding to alpha4beta1 in Ca2+/Mg2+ was used to identify nonselective antagonists among these four. These studies demonstrate that alpha4beta1 and alpha4beta7 have distinct binding properties for the same ligand, and binding parameters are dependent on the state of integrin activation in response to different divalent cations.
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- 2003
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15. Effects of VLA-4 antagonists in rat whole embryo culture.
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Spence S, Vetter C, Hagmann WK, Van Riper G, Williams H, Mumford RA, Lanza TJ, Lin LS, and Schmidt JA
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- Allantois abnormalities, Allantois embryology, Animal Husbandry, Animals, Antibodies immunology, Antibodies pharmacology, Culture Techniques, Female, Integrin alpha4beta1, Male, Mice, Placenta abnormalities, Placenta embryology, Placentation physiology, Pregnancy, Rats, Rats, Sprague-Dawley, Embryo, Mammalian drug effects, Integrins antagonists & inhibitors, Placentation drug effects, Receptors, Lymphocyte Homing antagonists & inhibitors
- Abstract
Background: Pharmacological antagonism of VLA-4 (Very Late Antigen 4, alpha(4)beta(1) integrin) has become an attractive target for the treatment of predominantly eosinophil mediated disease states such as asthma, allergic rhinitis, multiple sclerosis, rheumatoid arthritis, diabetes, and inflammatory bowel disease. Gene knockouts of the alpha(4)-integrin subunit of VLA-4 or its cell surface ligand, VCAM-1, however, have been shown to result in embryo-lethality in homozygous null mice due to defects in chorio-allantoic or epi-myocardial fusion. Although gene knockout phenotypes are not always manifested by pharmacological antagonism, those studies suggested that VLA-4 antagonists might cause embryo-lethality or drug-induced malformations., Methods: To test these concepts, early neurulating rat embryos were cultured by the methods of New ('78) after intra-coelomic microinjection of a VLA-4 blocking antibody or in the presence of small molecule VLA-4 antagonists., Results: Defects in chorio-allantoic fusion were induced after microinjection of VLA4 blocking antibody and after continuous exposure to small molecule antagonists. In a minority of affected embryos chorio-allantoic fusion was completely blocked whereas the majority of affected embryos had only superficial chorio-allantoic fusion and the allantois was enlarged and edematous. Although the allantoic mesoderm covered the trophoblasts of the chorionic plate and contained blood vessels there was only minimal invasion of the trophoblasts by the allantoic mesoderm. The lowest observed effect level generally correlated with the IC(approximately 95), as determined in 90% plasma., Discussion: Based on these data, VLA-4 antagonism might represent a significant risk to the developing embryo/fetus. In vitro exposure, however, is "constant" and does not take into account the elimination phase of these xenobiotics in vivo. Given the high concentrations required to elicit an effect, therapeutic blood levels in vivo may be several fold lower than those that affect the conceptus, depending on the tissue penetration of the compound and the route of administration. VLA-4 also exists in a range of conformations and activation states in vivo and the gene KOs and present studies do not define whether these developmental processes are dependent upon a particular activation state of VLA-4. Therefore, state-selective antagonists may have an improved embryonic safety profile. Additional studies will be required to determine potential effects of VLA-4 antagonists on embryo/fetal development in vivo., (Copyright 2002 Wiley‐Liss, Inc.)
- Published
- 2002
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16. Substituted 2-aminopyridines as inhibitors of nitric oxide synthases.
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Hagmann WK, Caldwell CG, Chen P, Durette PL, Esser CK, Lanza TJ, Kopka IE, Guthikonda R, Shah SK, MacCoss M, Chabin RM, Fletcher D, Grant SK, Green BG, Humes JL, Kelly TM, Luell S, Meurer R, Moore V, Pacholok SG, Pavia T, Williams HR, and Wong KK
- Subjects
- Aminopyridines pharmacology, Enzyme Inhibitors pharmacology, Humans, Structure-Activity Relationship, Aminopyridines chemical synthesis, Enzyme Inhibitors chemical synthesis, Nitric Oxide Synthase antagonists & inhibitors
- Abstract
A series of substituted 2-aminopyridines was prepared and evaluated as inhibitors of human nitric oxide synthases (NOS). 4,6-Disubstitution enhanced both potency and specificity for the inducible NOS with the most potent compound having an IC50 of 28 nM.
- Published
- 2000
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17. Inhibition of stromelysin-1 (MMP-3) by P1'-biphenylylethyl carboxyalkyl dipeptides.
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Esser CK, Bugianesi RL, Caldwell CG, Chapman KT, Durette PL, Girotra NN, Kopka IE, Lanza TJ, Levorse DA, MacCoss M, Owens KA, Ponpipom MM, Simeone JP, Harrison RK, Niedzwiecki L, Becker JW, Marcy AI, Axel MG, Christen AJ, McDonnell J, Moore VL, Olszewski JM, Saphos C, Visco DM, and Hagmann WK
- Subjects
- Animals, Arthritis drug therapy, Binding Sites, Cartilage drug effects, Crystallography, X-Ray, Dipeptides chemical synthesis, Dipeptides chemistry, Dipeptides metabolism, Disease Models, Animal, Gelatinases antagonists & inhibitors, Interleukin-1 administration & dosage, Interleukin-1 pharmacology, Magnetic Resonance Spectroscopy, Matrix Metalloproteinase 1, Matrix Metalloproteinase 2, Metalloendopeptidases antagonists & inhibitors, Mice, Models, Molecular, Molecular Structure, Protease Inhibitors chemical synthesis, Protease Inhibitors chemistry, Protease Inhibitors metabolism, Rabbits, Rats, Recombinant Proteins antagonists & inhibitors, Structure-Activity Relationship, Transferrin metabolism, Zinc chemistry, Zinc metabolism, Dipeptides pharmacology, Matrix Metalloproteinase Inhibitors, Protease Inhibitors pharmacology
- Abstract
Carboxyalkyl peptides containing a biphenylylethyl group at the P1' position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P1', a tert-butyl group at P2', and a methyl group at P3' produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P1-biphenyl inhibitor and the catalytic domain of MMP-3 is described. Inhibitors that contained halogenated biphenylylethyl residues at P1' proved to be superior in terms of enzyme potency and oral activity with 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl-1,5-pentane dioic acid 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a Ki of 10 nM against MMP-3 and an ED50 of 11 mg/kg po in the mouse pleural cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta injection in the rabbit) and chronic (rat adjuvant-induced arthritis and mouse collagen-induced arthritis) models of cartilage destruction but showed activity only in the MMP-3 injection model (ED50 = 6 mg/kg iv).
- Published
- 1997
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18. Inhibition of matrix metalloproteinases by N-carboxyalkyl peptides.
- Author
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Chapman KT, Kopka IE, Durette PL, Esser CK, Lanza TJ, Izquierdo-Martin M, Niedzwiecki L, Chang B, Harrison RK, and Kuo DW
- Subjects
- Amino Acid Sequence, Animals, Blood, Collagenases metabolism, Dipeptides metabolism, Dipeptides pharmacology, Drug Stability, Fibroblasts enzymology, Gelatinases antagonists & inhibitors, Gelatinases metabolism, Humans, Hydrogen-Ion Concentration, Matrix Metalloproteinase 2, Matrix Metalloproteinase 3, Matrix Metalloproteinase Inhibitors, Metalloendopeptidases metabolism, Mice, Molecular Sequence Data, Molecular Structure, Rabbits, Structure-Activity Relationship, Dipeptides chemical synthesis, Extracellular Matrix enzymology, Metalloendopeptidases antagonists & inhibitors
- Abstract
An extensive study of the requirements for effective binding of N-carboxyalkyl peptides to human stromelysin, collagenase, and to a lesser extent, gelatinase A has been investigated. These efforts afforded inhibitors generally in the 100-400 nM range for these matrix metalloproteinases. The most significant increase in potency was obtained with the introduction of a beta-phenylethyl group at the P1' position, suggesting a small hydrophobic channel into the S1' subsite of stromelysin. One particular compound, N-[1(R)-carboxyethyl]-alpha(S)-(2-phenylethyl)glycyl-L-leucine,N- phenylamide (79a), is relatively selective for rabbit stromelysin with a K(i) = 6.5 nM and may prove useful for elucidating the role of endogenously-produced stromelysin in lapine models of tissue degradation.
- Published
- 1993
- Full Text
- View/download PDF
19. Substituted 4,6-diaminoquinolines as inhibitors of C5a receptor binding.
- Author
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Lanza TJ, Durette PL, Rollins T, Siciliano S, Cianciarulo DN, Kobayashi SV, Caldwell CG, Springer MS, and Hagmann WK
- Subjects
- Aminoquinolines chemical synthesis, Cell Degranulation drug effects, Cell Degranulation immunology, Complement C5a antagonists & inhibitors, Humans, In Vitro Techniques, Leukotriene B4 metabolism, N-Formylmethionine Leucyl-Phenylalanine metabolism, Neutrophils drug effects, Receptor, Anaphylatoxin C5a, Structure-Activity Relationship, Aminoquinolines pharmacology, Complement C5a metabolism, Receptors, Complement antagonists & inhibitors
- Abstract
The anaphylatoxin C5a is implicated in a number of inflammatory diseases. It is a highly cationic protein with 13 of 74 amino acids being either arginine or lysine. A search focusing on positively charged molecules, particularly amine-containing functionalities, led to the discovery of substituted 4,6-diaminoquinolines 1 [N,N'-bis(4-amino-2-methyl-6-quinolyl)urea] and 7 [6-N-(2-chlorocinnamoyl)-4,6-diamino-2-methylquinoline] as inhibitors of C5a receptor binding. These two compounds inhibited the binding of radiolabeled C5a to its receptor isolated from human neutrophils with IC50's = 3.3 and 12 micrograms/mL, respectively. Our efforts to enhance their potencies by chemical modification revealed a narrow profile of potency for effective C5a receptor binding inhibition.
- Published
- 1992
- Full Text
- View/download PDF
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