ABSTRACT
A new series of epiminocyclohepta[b]indoles with potent 5-HT(6) antagonist activity were discovered and optimized using in vitro protocols. One compound from this series was progressed to advanced pharmacokinetic (PK) studies followed by 5-HT(6) receptor occupancy studies. The compound was found to have excellent oral absorption, a highly favorable PK profile and demonstrated pharmacodynamic interaction with the 5-HT(6) receptor as shown by ex vivo autoradiography.
Subject(s)
Indoles/pharmacokinetics , Receptors, Serotonin/metabolism , Serotonin Antagonists , Administration, Oral , Animals , Caco-2 Cells , Humans , Indoles/administration & dosage , Indoles/chemistry , Indoles/pharmacology , Molecular Structure , Protein Binding/drug effects , Purinergic P1 Receptor Antagonists , Rats , Rats, Sprague-Dawley , Receptors, Serotonin/chemistry , Serotonin Antagonists/administration & dosage , Serotonin Antagonists/pharmacokinetics , Serotonin Antagonists/pharmacology , Structure-Activity RelationshipABSTRACT
Serotonin is known to have anorectic properties through centrally acting mechanisms. Three serotonin receptors have been implicated in mediating these effects: 5-HT(1B), 5-HT(2C) and 5-HT(6). Hypophagic effects are elicited through agonism of the former two receptors, whereas antagonism of the 5-HT(6) receptor appears to have an anorectic effect. All three targets have been validated through extensive studies including knockout mice and selective ligand assessment. 5-HT(1B) receptor agonists have limited utility due to mechanism-based side effects, whereas 5-HT(2C) receptor agonists suffer from challenges associated with selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. 5-HT(6) receptor antagonists appear to offer great promise, although the mechanisms through which they reduce food intake and body weight are not fully understood.
Subject(s)
Obesity/drug therapy , Receptors, Serotonin/metabolism , Serotonin Antagonists/pharmacology , Serotonin Antagonists/therapeutic use , Serotonin Receptor Agonists/pharmacology , Serotonin Receptor Agonists/therapeutic use , Animals , Humans , Molecular Targeted Therapy , Obesity/metabolism , Serotonin/metabolismABSTRACT
We report the development and characterization of compound 22 (MK-5046), a potent, selective small molecule agonist of BRS-3 (bombesin receptor subtype-3). In pharmacological testing using diet-induced obese mice, compound 22 caused mechanism-based, dose-dependent reductions in food intake and body weight.
ABSTRACT
A new series of 5-(pyridinon-1-yl)indazoles with MCH-1 antagonist activity were synthesized. Potential cardiovascular risk for these compounds was assessed based upon their interaction with the hERG potassium channel in a mini-patch clamp assay. Selected compounds were studied in a 5-day diet-induced obese mouse model to evaluate their potential use as weight loss agents. Structural modification of the 5-(pyridinon-1-yl)indazoles to give 5-(furopyridinon-5-yl)indazoles provided compounds with enhanced pharmacokinetic properties and improved efficacy.
Subject(s)
Indazoles/pharmacology , Obesity/drug therapy , Receptors, Pituitary Hormone/antagonists & inhibitors , Animals , Anti-Obesity Agents/chemistry , Anti-Obesity Agents/pharmacology , Cardiovascular Diseases/chemically induced , Ether-A-Go-Go Potassium Channels/drug effects , Humans , Indazoles/pharmacokinetics , Indazoles/therapeutic use , Mice , Structure-Activity RelationshipABSTRACT
A new series of 4-aryl-1-(indazol-5-yl)pyridin-2(1H)ones possessing MCH-1 receptor antagonism is presented. Suzuki coupling of boronic acids with key triflate 6 allowed rapid generation of a range of analogs. The SAR of the MCH-1 receptor was explored with a variety of aryl and heterocyclic moieties. Selected compounds were studied in a five-day diet induced obese mouse model to evaluate their potential use as weight loss agents.
Subject(s)
Anti-Obesity Agents/chemistry , Obesity/drug therapy , Pyridines/chemistry , Receptors, Pituitary Hormone/antagonists & inhibitors , Animals , Anti-Obesity Agents/pharmacology , Mice , Pyridines/pharmacology , Structure-Activity RelationshipABSTRACT
A new series of tetrahydrocarbolines with potent MCH-1 antagonist activity were synthesized, using a conformationally constrained design approach towards optimizing pharmacokinetic properties. Two compounds from this series were progressed to a 5-day diet-induced obesity mouse screening model to evaluate their potential as weight loss agents. Both compounds produced a highly significant reduction in weight, which was attributed to their improved pharmacokinetic profile.
Subject(s)
Anti-Obesity Agents/chemistry , Carbolines/chemistry , Obesity/drug therapy , Receptors, Pituitary Hormone/antagonists & inhibitors , Animals , Anti-Obesity Agents/pharmacology , Body Weight/drug effects , Carbolines/pharmacology , Carbolines/therapeutic use , Mice , Structure-Activity RelationshipABSTRACT
SAR around non-peptidic potent bombesin receptor subtype-3 (BRS-3) agonist lead 2 is presented. Attempts to replace the carboxylic acid with heterocyclic isosteres to improve oral bioavailability and brain penetration are described.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Imidazoles/chemistry , Receptors, Bombesin/agonists , Administration, Oral , Animals , Anti-Obesity Agents/chemistry , Anti-Obesity Agents/therapeutic use , Brain/metabolism , Humans , Imidazoles/chemical synthesis , Imidazoles/therapeutic use , Mice , Obesity/drug therapy , Rats , Receptors, Bombesin/metabolism , Structure-Activity RelationshipABSTRACT
This Letter describes a series of potent and selective BRS-3 agonists containing a biarylethylimidazole pharmacophore. Extensive SAR studies were carried out with different aryl substitutions. This work led to the identification of a compound 2-{2-[4-(pyridin-2-yl)phenyl]ethyl}-5-(2,2-dimethylbutyl)-1H-imidazole 9 with excellent binding affinity (IC(50)=18 nM, hBRS-3) and functional agonist activity (EC(50)=47 nM, 99% activation). After oral administration, compound 9 had sufficient exposure in diet induced obese mice to demonstrate efficacy in lowering food intake and body weight via BRS-3 activation.
Subject(s)
Imidazoles/chemistry , Imidazoles/therapeutic use , Obesity/drug therapy , Receptors, Bombesin/agonists , Receptors, Bombesin/metabolism , Animals , Body Weight/drug effects , Eating/drug effects , Humans , Imidazoles/pharmacokinetics , Mice , Rats , Structure-Activity RelationshipABSTRACT
We report SAR studies on a novel non-peptidic bombesin receptor subtype-3 (BRS-3) agonist lead series derived from high-throughput screening hit RY-337. This effort led to the discovery of compound 22e with significantly improved potency at both rodent and human BRS-3.
Subject(s)
Drug Discovery , Imidazoles/chemistry , Imidazoles/pharmacology , Receptors, Bombesin/agonists , Animals , Biological Availability , Humans , Imidazoles/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
Inhibition of rho kinase (ROCK) has been recognized as an important target for a number of diseases, including glaucoma. Herein we report SAR development around two hits from a kinase library that led to the discovery of the ROCK inhibitor compound 38. In vitro and in vivo analysis of this compound, including its effects in a monkey model of glaucoma will be discussed.
