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Your search keyword '"Godonis H"' showing total 3 results
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3 results on '"Godonis H"'

1. Synthesis and Antiobesity Properties of 6-(4-Chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (BMS-814580): A Highly Efficacious Melanin Concentrating Hormone Receptor 1 (MCHR1) Inhibitor.

Author

Ahmad S, Washburn WN, Hernandez AS, Bisaha S, Ngu K, Wang W, Pelleymounter MA, Longhi D, Flynn N, Azzara AV, Rohrbach K, Devenny J, Rooney S, Thomas M, Glick S, Godonis H, Harvey S, Zhang H, Gemzik B, Janovitz EB, Huang C, Zhang L, Robl JA, and Murphy BJ

Subjects
Animals, Anti-Obesity Agents pharmacokinetics, Anti-Obesity Agents pharmacology, Dogs, Halogenation, Humans, Macaca fascicularis, Male, Mice, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Rats, Receptors, Somatostatin metabolism, Structure-Activity Relationship, Anti-Obesity Agents chemistry, Anti-Obesity Agents therapeutic use, Obesity drug therapy, Pyrimidines chemistry, Pyrimidines therapeutic use, Receptors, Somatostatin antagonists & inhibitors
Abstract

The potent MCHR1 in vitro and in vivo antagonist activity of a series of cyclic tertiary alcohols derived from compound 2b is described. Subsequent pharmacokinetic and pharmacodynamic studies identified BMS-814580 (compound 10) as a highly efficacious antiobesity agent with a relatively clean in vitro and in vivo safety profile.

Published
2016
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2. Non-basic azolotriazinone MCHR1 antagonists for the treatment of obesity: An empirical brain-exposures-driven candidate selection for in vivo efficacy studies.

Author

Devasthale P, Wang W, Mignone J, Renduchintala K, Radhakrishnan S, Dhanapal J, Selvaraj J, Kuppusamy R, Pelleymounter MA, Longhi D, Huang N, Flynn N, Azzara AV, Rohrbach K, Devenny J, Rooney S, Thomas M, Glick S, Godonis H, Harvey S, Cullen MJ, Zhang H, Caporuscio C, Stetsko P, Grubb M, Huang C, Zhang L, Freeden C, Murphy BJ, Robl JA, and Washburn WN

Subjects
Animals, Brain metabolism, Dose-Response Relationship, Drug, Humans, Molecular Structure, Obesity metabolism, Rats, Structure-Activity Relationship, Triazines administration & dosage, Triazines chemistry, Brain drug effects, Obesity drug therapy, Receptors, Somatostatin antagonists & inhibitors, Triazines pharmacology
Abstract

Non-basic azolotriazinones were explored using an empirical free brain exposures-driven approach to identify potent MCHR1 antagonists for evaluation in in vivo efficacy studies. An optimized lead from this series, 1j (rMCHR1 Ki=1.8 nM), demonstrated a 6.9% reduction in weight gain relative to vehicle in a rat model at 30 mg/kg after 4 days of once-daily oral treatment as a glycine prodrug. Despite a promising efficacy profile, an assessment of the biliary toxicity risk of this compound rendered this compound non-progressible., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2015
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3. Dihydropyrrolopyrazol-6-one MCHR1 antagonists for the treatment of obesity: Insights on in vivo efficacy from a novel FLIPR assay setup.

Author

Devasthale P, Wang W, Hernandez AS, Moore F, Renduchintala K, Sridhar R, Pelleymounter MA, Longhi D, Huang N, Flynn N, Azzara AV, Rohrbach K, Devenny J, Rooney S, Thomas M, Glick S, Godonis H, Harvey S, Cullen MJ, Zhang H, Caporuscio C, Stetsko P, Grubb M, Huang C, Zhang L, Freeden C, Li YX, Murphy BJ, Robl JA, and Washburn WN

Subjects
Animals, Anti-Obesity Agents pharmacokinetics, Anti-Obesity Agents pharmacology, Anti-Obesity Agents therapeutic use, Half-Life, Humans, Obesity drug therapy, Protein Binding, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Pyrazoles therapeutic use, Rats, Rats, Sprague-Dawley, Receptors, Somatostatin metabolism, Structure-Activity Relationship, Weight Loss drug effects, Anti-Obesity Agents chemistry, Pyrazoles chemistry, Receptors, Somatostatin antagonists & inhibitors
Abstract

Our investigation of the structure-activity and structure-liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in vivo efficacy. The in vitro and exposure profiles of dihydropyrrolopyrazol-6-ones 1b and 1e were comparable to that of the thienopyrimidinone counterparts 41 and 43 except for a much faster MCHR1 apparent off-rate. The greatly diminished dihydropyrrolopyrazol-6-one anti-obesity response may be the consequence of this rapid off-rate., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2015
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