ABSTRACT
MK-4256, a tetrahydro-ß-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-ß-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.
Subject(s)
Carbolines/chemistry , Carbolines/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Animals , Carbolines/chemical synthesis , Dogs , Dose-Response Relationship, Drug , Humans , Mice , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-à-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, 3A, was identified from this SAR effort. As a potent sstr3 antagonist, 3A was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, 3A elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress.
ABSTRACT
A structure-activity relationship study of the imidazolyl-ß-tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice.
ABSTRACT
We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Compound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obesity efficacy in a mouse model. However, the efficacy is not completely mediated through MC4R. Additional SAR studies led to the discovery of compound 32, which is more potent at MC4R. Compound 32 demonstrates MC4R mediated anti-obesity efficacy in rodent models.
Subject(s)
Obesity/drug therapy , Receptor, Melanocortin, Type 4/agonists , Triazoles/pharmacology , Animals , Chromatography, High Pressure Liquid , Disease Models, Animal , Mice , Mice, Knockout , Molecular Structure , Rats , Receptor, Melanocortin, Type 4/genetics , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/therapeutic useABSTRACT
Design, syntheses and structure-activity relationships of N-acetylated piperazine privileged structures containing MC4R agonist compounds were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties.
Subject(s)
Ligands , Receptor, Melanocortin, Type 4/agonists , Animals , Humans , Piperazine , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity RelationshipABSTRACT
Design, synthesis, and SAR of a series of 3H-spiro[isobenzofuran-1,4'-piperidine] based compounds as potent, selective and orally bioavailable melanocortin subtype-4 receptor (MC4R) agonists are disclosed.
Subject(s)
Piperidines/chemistry , Receptor, Melanocortin, Type 4/agonists , Administration, Oral , Animals , Brain/metabolism , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , Molecular Conformation , Piperidines/chemical synthesis , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/metabolism , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models.
Subject(s)
Amides/chemistry , Anti-Obesity Agents/chemistry , Obesity/drug therapy , Pyrrolidines/chemistry , Receptor, Melanocortin, Type 4/agonists , Spiro Compounds/chemistry , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/therapeutic use , Body Weight/drug effects , Humans , Mice , Mice, Knockout , Pyrrolidines/pharmacokinetics , Pyrrolidines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/metabolism , Spiro Compounds/pharmacokinetics , Spiro Compounds/therapeutic use , Structure-Activity RelationshipABSTRACT
We report the design, synthesis and properties of spiroindane based compound 1, a potent, selective, orally bioavailable, non-peptide melanocortin subtype-4 receptor agonist. Compound 1 shows excellent erectogenic activity in the rodent models.
Subject(s)
Erectile Dysfunction/drug therapy , Indans/chemistry , Indans/therapeutic use , Receptor, Melanocortin, Type 4/agonists , Receptor, Melanocortin, Type 4/metabolism , Spiro Compounds/chemistry , Spiro Compounds/therapeutic use , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Haplorhini , Humans , Indans/pharmacokinetics , Indans/pharmacology , Male , Mice , Molecular Structure , Protein Binding , Rats , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , 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
Bombesin receptor subtype 3 (BRS-3) is a G protein coupled receptor whose natural ligand is unknown. We developed potent, selective agonist (Bag-1, Bag-2) and antagonist (Bantag-1) ligands to explore BRS-3 function. BRS-3-binding sites were identified in the hypothalamus, caudal brainstem, and several midbrain nuclei that harbor monoaminergic cell bodies. Antagonist administration increased food intake and body weight, whereas agonists increased metabolic rate and reduced food intake and body weight. Prolonged high levels of receptor occupancy increased weight loss, suggesting a lack of tachyphylaxis. BRS-3 agonist effectiveness was absent in Brs3(-/Y) (BRS-3 null) mice but was maintained in Npy(-/-)Agrp(-/-), Mc4r(-/-), Cnr1(-/-), and Lepr(db/db) mice. In addition, Brs3(-/Y) mice lost weight upon treatment with either a MC4R agonist or a CB1R inverse agonist. These results demonstrate that BRS-3 has a role in energy homeostasis that complements several well-known pathways and that BRS-3 agonists represent a potential approach to the treatment of obesity.