RESUMO
Novel potent and selective 5,6,5- and 5,5,6-tricyclic pyrrolidine dipeptidyl peptidase IV (DPP-4) inhibitors were identified. Structure-activity relationship (SAR) efforts focused on improving the intrinsic DPP-4 inhibition potency, increasing protease selectivity, and demonstrating clean ion channel and cytochrome P450 profiles while trying to achieve a pharmacokinetic profile suitable for once weekly dosing in humans.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Descoberta de Drogas , Pirrolidinas/farmacologia , Animais , Cristalografia por Raios X , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Cães , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Hipoglicemiantes/farmacologia , Piranos/farmacologia , Animais , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Inibidores da Dipeptidil Peptidase IV/toxicidade , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Compostos Heterocíclicos com 2 Anéis/toxicidade , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/toxicidade , Piranos/síntese química , Piranos/farmacocinética , Piranos/toxicidade , Relação Estrutura-AtividadeRESUMO
Molecular modeling was used to improve potency of the cyclohexylamine series. In addition, a 3-D QSAR method was used to gain insight for reducing off-target DPP-8/9 activities. Compounds 3, 4, and 5 were synthesized and found to be potent DPP-4 inhibitors, in particular 4 and 5 are designed to be highly selective against off-target DASH enzymes while maintaining potency on DPP-4.
Assuntos
Inibidores da Dipeptidil Peptidase IV , Inibidores de Proteases/farmacologia , Pirimidinas/farmacologia , Desenho de Fármacos , Modelos Moleculares , Inibidores de Proteases/química , Pirimidinas/química , Relação Quantitativa Estrutura-AtividadeRESUMO
Following the discovery of N-acyl-1,4-diazepan-2-one as a novel pharmacophore for potent and selective DPP-4 inhibitors, optimization of this new lead with different substitution on the seven-membered ring resulted in several highly potent and selective, orally bioavailable, and efficacious DPP-4 inhibitors, such as 3R-methyl-1-cyclopropyl-1,4-diazepan-2-one derivative 9i (DPP-4 IC(50)=8.0 nM) and 3R,6R-dimethyl-1,4-diazepan-2-one derivative 14a (DPP-4 IC(50)=9.7 nM).
Assuntos
Azepinas/síntese química , Química Farmacêutica/métodos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Administração Oral , Animais , Azepinas/farmacologia , Desenho de Fármacos , Concentração Inibidora 50 , Masculino , Camundongos , Modelos Químicos , Conformação Molecular , Ratos , Ratos Sprague-DawleyRESUMO
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
Molecular modeling was used to design a rigid analog of sitagliptin 1. The X-ray crystal structure of sitagliptin bound to DPP-4 suggested that the central beta-amino butyl amide moiety could be replaced with a cyclohexylamine group. This was confirmed by structural analysis and the resulting analog 2a was synthesized and found to be a potent DPP-4 inhibitor (IC(50)=21 nM) with excellent in vivo activity and pharmacokinetic profile.
Assuntos
Inibidores de Adenosina Desaminase , Cicloexilaminas/química , Inibidores da Dipeptidil Peptidase IV , Glicoproteínas/antagonistas & inibidores , Inibidores da Protease de HIV/farmacologia , Pirazinas/farmacologia , Triazóis/farmacologia , Administração Oral , Sítios de Ligação , Cristalografia por Raios X , Dipeptidil Peptidase 4 , Desenho de Fármacos , Inibidores da Protease de HIV/síntese química , Humanos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Pirazinas/química , Fosfato de Sitagliptina , Triazóis/químicaRESUMO
Replacement of the triazolopiperazine ring of sitagliptin (DPP-4 IC(50)=18nM) with 3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one gave dipeptidyl peptidase IV (DPP-4) inhibitor 1 which is potent (DPP-4 IC(50)=2.6nM), selective, and efficacious in an oral glucose tolerance test in mice. It was selected for extensive preclinical development as a potential back-up candidate to sitagliptin.
Assuntos
Azepinas/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV , Hipoglicemiantes/química , Inibidores de Proteases/química , Animais , Azepinas/uso terapêutico , Cristalografia por Raios X , Dipeptidil Peptidase 4/química , Hipoglicemiantes/uso terapêutico , Inibidores de Proteases/uso terapêutico , Conformação Proteica , Pirazinas/química , Pirazinas/uso terapêutico , Ratos , Ratos Endogâmicos , Fosfato de Sitagliptina , Triazóis/química , Triazóis/uso terapêuticoRESUMO
Dipeptidyl peptidase IV (DP-IV) is a cell surface serine dipeptidase that is involved in the regulation of the incretin hormones, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). There is accumulating evidence that other members of the glucagon family of peptides are also endogenous substrates for this enzyme. To identify candidate substrates for DP-IV, a mass spectrometry-based protease assay was developed that measures cleavage efficiencies (kcat/Km) of polypeptides in a mixture, using only a few picomoles of each substrate and physiological amounts of enzyme in a single kinetic experiment. Oxyntomodulin and the growth hormone-(1-43) fragment were identified as new candidate in vivo substrates. Pituitary adenylate cyclase-activating polypeptide-(1-38) (PACAP38), a critical mediator of lipid and carbohydrate metabolism, was also determined to be efficiently processed by DP-IV in vitro. The catabolism of exogenously administered PACAP38 in wild type and DP-IV-deficient C57Bl/6 mice was monitored by tandem mass spectrometry. Animals lacking DP-IV exhibited a significantly slower clearance of the circulating peptide with virtually complete suppression of the inactive DP-IV metabolite, PACAP-(3-38). These in vivo results suggest that DP-IV plays a major role in the degradation of circulating PACAP38.