RESUMO
The synthesis of a novel class of piperazine benzamide (reverse amides) targeting the human ß3-adrenergic receptor for the treatment of overactive bladder (OAB) is described. The SAR studies directed towards maintaining well established ß3 potency and selectivities while improving the overall pharmacokinetic profile in the reverse amide class will be evaluated. The results and consequences associated with functional activity at the norepinephrine transporter (NET) will also be discussed.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Piperazinas/farmacologia , Bexiga Urinária Hiperativa/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 3/química , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Humanos , Piperazinas/química , Piperazinas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
The discovery of vibegron, a potent and selective human ß3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical ß3-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived ß3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure-activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Pirimidinonas/uso terapêutico , Pirrolidinas/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/toxicidade , Animais , Células CHO , Cricetinae , Cricetulus , Descoberta de Drogas , Feminino , Humanos , Lipidoses/induzido quimicamente , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Moleculares , Pirimidinonas/farmacocinética , Pirimidinonas/toxicidade , Pirrolidinas/farmacocinética , Pirrolidinas/toxicidade , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Relação Estrutura-Atividade , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos , Difração de Raios XRESUMO
Two high-throughput screening hits were investigated for SAR against human factor IXa. Both hits feature a benzamide linked to a [6-5]-heteroaryl via an alkyl amine. In the case where this system is a benzimidazolyl-ethyl amine the binding potency for the hit was improved >500-fold, from 9 µM to 0.016 µM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2 µM to 0.09 µM. X-ray crystal structures were obtained for an example of each class which improved understanding of the binding, and will enable further drug discovery efforts.
Assuntos
Anticoagulantes/química , Anticoagulantes/farmacologia , Fator IXa/antagonistas & inibidores , Sítios de Ligação , Descoberta de Drogas , Humanos , Modelos Moleculares , Estrutura Molecular , Conformação ProteicaRESUMO
A series of conformationally restricted acetanilides were synthesized and evaluated as ß3-adrenergic receptor agonists (ß3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine ß3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent ß3-AR mediated responses in a rat bladder hyperactivity model.
Assuntos
Acetanilidas/síntese química , Acetanilidas/farmacologia , Agonistas de Receptores Adrenérgicos beta 3/síntese química , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Bexiga Urinária Hiperativa/tratamento farmacológico , Acetanilidas/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Animais , Células CHO , Cricetinae , Cricetulus , Desenho de Fármacos , Humanos , Espectroscopia de Ressonância Magnética , Conformação MolecularRESUMO
A series of amide derived beta(3)-adrenergic receptor (AR) agonists is described. The discovery and optimization of several series of compounds derived from 1, is used to lay the SAR foundation for second generation beta(3)-AR agonists for the treatment of overactive bladder.
Assuntos
Acetamidas/farmacologia , Agonistas de Receptores Adrenérgicos beta 3 , Antagonistas Adrenérgicos beta/farmacologia , Benzamidas/farmacologia , Acetamidas/farmacocinética , Antagonistas Adrenérgicos beta/farmacocinética , Animais , Benzamidas/farmacocinética , Roedores , Relação Estrutura-AtividadeRESUMO
The discovery and structure-activity relationship of 1,2-diarylimidazole piperazine carboxamides bearing polar side chains as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described. Optimization of this series resulted in the discovery of isopropyl carboxamide 40, a CCK1R agonist with sub-nanomolar functional and binding activity as well as excellent potency in a mouse overnight food intake reduction assay.
Assuntos
Fármacos Antiobesidade/farmacologia , Benzodiazepinas/farmacologia , Indóis/farmacologia , Obesidade/tratamento farmacológico , Receptor de Colecistocinina A/agonistas , Tiazóis/farmacologia , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/química , Benzodiazepinas/síntese química , Benzodiazepinas/química , Quimiocinas CC , Humanos , Indóis/síntese química , Indóis/química , Metilaminas/síntese química , Metilaminas/química , Metilaminas/farmacologia , Camundongos , Piperazina , Piperazinas/química , Receptores da Colecistocinina/agonistas , Receptores da Colecistocinina/química , Tiazóis/síntese química , Tiazóis/químicaRESUMO
Substituted 3-aminopiperidines 3 were evaluated as DPP-4 inhibitors. The inhibitors showed good DPP-4 potency with superb selectivity over other peptidases (QPP, DPP8, and DPP9). Selected DPP-4 inhibitors were further evaluated for their hERG potassium channel, calcium channel, Cyp2D6, and pharmacokinetic profiles.
Assuntos
Inibidores da Dipeptidil Peptidase IV , Piperidinas/química , Piperidinas/farmacologia , Animais , Área Sob a Curva , Disponibilidade Biológica , Meia-Vida , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Estrutura Molecular , Piperidinas/sangue , Ratos , Relação Estrutura-AtividadeRESUMO
A series of beta-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogues led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)butanamide (6), a potent, orally active DPP-4 inhibitor (IC(50) = 6.3 nM) with excellent selectivity, oral bioavailability in preclinical species, and in vivo efficacy in animal models. Compound 6 was selected for further characterization as a potential new treatment for type 2 diabetes.