RESUMO
The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family and a more modest 30- to 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP receptor dependent cAMP accumulation assays. 5c had an excellent PK profile across species. Enterohepatic recirculation most probably contributes to a concentration-time profile after oral administration in the cynomolgus monkey that showed a very low peak-to-trough ratio. Following the identification of an acceptable solid form, 5c was selected for further development for the treatment of PAH.
Assuntos
Acetatos/uso terapêutico , Carbamatos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Receptores de Prostaglandina/agonistas , Acetatos/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Carbamatos/farmacocinética , Descoberta de Drogas , Ratos , Relação Estrutura-AtividadeRESUMO
The design and optimization of a novel trans-1,4-dioxycyclohexane GPR119 agonist series is described. A lead compound 21 was found to be a potent and efficacious GPR119 agonist across species, and possessed overall favorable pharmaceutical properties. Compound 21 demonstrated robust acute and chronic regulatory effects on glycemic parameters in the diabetic or non-diabetic rodent models.
Assuntos
Cicloexanos/química , Cicloexanos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Receptores Acoplados a Proteínas G/agonistas , Administração Oral , Animais , Glicemia/análise , Cicloexanos/administração & dosagem , Cicloexanos/farmacocinética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Masculino , Camundongos , Ratos Sprague-Dawley , Ratos Zucker , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
The design and synthesis of two closely related series of prostacyclin receptor agonist compounds that showed excellent human IP receptor potency and efficacy is described. Compounds from this series showed in vivo activity after SC dosing in the monocrotaline model of PAH in rat.
Assuntos
Descoberta de Drogas , Hipertensão Pulmonar/tratamento farmacológico , Receptores de Prostaglandina/agonistas , Animais , Humanos , Hipertensão Pulmonar/induzido quimicamente , Monocrotalina , Agregação Plaquetária/efeitos dos fármacos , Ratos , Receptores de Prostaglandina/metabolismoRESUMO
A series of 5-fluoro-4,6-dialkoxypyrimidine GPR119 modulators were discovered and optimized for in vitro agonist activity. A lead molecule was identified that has improved agonist efficacy relative to our clinical compound (APD597) and possesses reduced CYP2C9 inhibitory potential. This optimized lead was found to be efficacious in rodent models of glucose control both alone and in combination with a Dipeptidyl peptidase-4 (DPP-4) inhibitor.
