RESUMO
Identification of a series of imidazo[4,5-c]pyridin-4-one derivatives that act as dual angiotensin II type 1 (AT1) receptor antagonists and peroxisome proliferator-activated receptor-γ (PPARγ) partial agonists is described. Starting from a known AT1 antagonist template, conformational restriction was introduced by incorporation of an indane ring that when combined with appropriate substitution at the imidazo[4,5-c]pyridin-4-one provided novel series 5 possessing the desired dual activity. The mode of interaction of this series with PPARγ was corroborated through the X-ray crystal structure of 12b bound to the human PPARγ ligand binding domain. Modulation of activity at both receptors through substitution at the pyridone nitrogen led to the identification of potent dual AT1 antagonists/PPARγ partial agonists. Among them, 21b was identified possessing potent dual pharmacology (AT1 IC(50) = 7 nM; PPARγ EC(50) = 295 nM, 27% max) and good ADME properties.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , PPAR gama/metabolismo , Piridinas/síntese química , Piridinas/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzoatos/química , Benzoatos/farmacologia , Cristalografia por Raios X , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Concentração Inibidora 50 , Modelos Moleculares , Conformação Molecular , PPAR gama/agonistas , Ligação Proteica/efeitos dos fármacos , Piridinas/química , Piridonas/síntese química , Piridonas/química , Piridonas/farmacologia , TelmisartanRESUMO
Aiming to improve upon previously disclosed Factor Xa inhibitors, a series of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides were explored with the intent of increasing the projected human half-life versus 5 (projected human t(1/2)=6 h). A stereospecific route to compounds containing a 4-aryl-4-hydroxypyrrolidine scaffold was developed, resulting in several compounds that demonstrated an increase in the half-life as well as an increase in the in vitro potency compared to 5. Reported herein is the discovery of 26, containing a (2R,4S)-4-hydroxy-4-(2,4-difluorophenyl)-pyrrolidine scaffold, which is a selective, orally bioavailable, efficacious Factor Xa inhibitor that appears suitable for a once-daily dosing (projected human t(1/2)=23 h).
Assuntos
Pirrolidinas/farmacologia , Administração Oral , Cristalografia por Raios X , Meia-Vida , Humanos , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacocinéticaRESUMO
Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-γ (PPARγ) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPARγ confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPARγ activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC(50) = 1.6 nM) with partial PPARγ agonism (EC(50) = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Anti-Hipertensivos/síntese química , Hipoglicemiantes/síntese química , Imidazóis/síntese química , PPAR gama/agonistas , Piridinas/síntese química , Administração Oral , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Disponibilidade Biológica , Glicemia/análise , Cristalografia por Raios X , Agonismo Parcial de Drogas , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Resistência à Insulina , Masculino , Modelos Moleculares , Piridinas/química , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Endogâmicos SHR , Estereoisomerismo , Relação Estrutura-Atividade , Ativação Transcricional , Triglicerídeos/sangueRESUMO
A novel series of pyrrolidine-1,2-dicarboxamides was discovered as factor Xa inhibitors using structure-based drug design. This series consisted of a neutral 4-chlorophenylurea P1, a biphenylsulfonamide P4 and a D-proline scaffold (1, IC(50) = 18 nM). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa (13, IC(50) = 0.38 nM), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.