RESUMO
In our effort to find potent, orally bioavailable CGRP receptor antagonists for the treatment of migraine, a novel series based on a pyridinone template was investigated. After optimizing the privileged structure and the placement of the attached phenyl ring, systematic SAR was carried out on both the N-alkyl and C-5 aryl substituents. Several analogs with good potency and pharmacokinetic profiles were identified.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Piridonas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Meia-Vida , Piridonas/administração & dosagem , Piridonas/química , Piridonas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Antagonism of the bradykinin B(1) receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists incorporating alpha-hydroxy amides were designed that display low-nanomolar affinity for the human bradykinin B(1) receptor and good bioavailability in the rat and dog. In addition, these functionally active compounds show high passive permeability and low susceptibility to phosphoglycoprotein mediated efflux, predictive of good CNS exposure.
Assuntos
Amidas/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Amidas/química , Amidas/farmacocinética , Animais , Disponibilidade Biológica , Barreira Hematoencefálica , Inibidores das Enzimas do Citocromo P-450 , Cães , Meia-Vida , Humanos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Antagonism of the bradykinin B1 receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists were designed that display low-nanomolar affinity for the human bradykinin B1 receptor and good bioavailability in the rat.
Assuntos
Amidas/síntese química , Analgésicos/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Antagonistas de Receptor B1 da Bradicinina , Ciclopropanos/síntese química , Piridinas/síntese química , Amidas/química , Amidas/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Disponibilidade Biológica , Ciclopropanos/química , Ciclopropanos/farmacologia , Desenho de Fármacos , Humanos , Conformação Molecular , Piridinas/química , Piridinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Optimization of a previously reported thrombin inhibitor, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-trans-4-aminocyclohexylmethylamide (1), by replacing the aminocyclohexyl P1 group provided a new lead structure, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenzylamide (2), with improved potency (K(i) = 0.49 nM for human thrombin, 2x APTT = 0.37 microM in human plasma) and pharmacokinetic properties (F = 39%, iv T(1/2) = 13 h in dogs). An effective strategy for reducing plasma protein binding of 2 and improving efficacy in an in vivo thrombosis model in rats was to replace the lipophilic fluorenyl group in P3 with an azafluorenyl group. Systematic investigation of all possible azafluorenyl P3 isomers and azafluorenyl-N-oxide analogues of 2 led to the identification of an optimal compound, 3-aza-9-hydroxyfluoren-9(R)-ylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenzylamide (19b), with high potency (K(i) = 0.40 nM, 2x APTT = 0.18 microM), excellent pharmacokinetic properties (F = 55%, T(1/2) = 14 h in dogs), and complete efficacy in the in vivo thrombosis model in rats (inhibition of FeCl(3)-induced vessel occlusions in six of six rats receiving an intravenous infusion of 10 microg/kg/min of 19b). The stereochemistry of the azafluorenyl group in 19b was determined by X-ray crystallographic analysis of its N-oxide derivative (23b) bound in the active site of human thrombin.
Assuntos
Fluorenos/síntese química , Prolina/análogos & derivados , Prolina/síntese química , Trombina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Cristalografia por Raios X , Cães , Fluorenos/química , Fluorenos/farmacologia , Meia-Vida , Humanos , Técnicas In Vitro , Macaca mulatta , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Prolina/química , Prolina/farmacologia , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Naphthyridine 7 inhibits the strand transfer of the integration process catalyzed by integrase with an IC50 of 10 nM and inhibits 95% of the spread of HIV-1 infection in cell culture at 0.39 microM. It does not exhibit cytotoxicity in cell culture at < or =12.5 microM and shows a good pharmacokinetic profile when dosed orally to rats. The antiviral activity of 7 and its effect on integration were confirmed using viruses with specific integrase mutations.
Assuntos
Fármacos Anti-HIV/síntese química , Inibidores de Integrase de HIV/síntese química , HIV-1/efeitos dos fármacos , Naftiridinas/síntese química , Administração Oral , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Humanos , Injeções Intravenosas , Naftiridinas/química , Naftiridinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.
Assuntos
Acetamidas/farmacocinética , Anticoagulantes/farmacocinética , Inibidores de Proteases/síntese química , Pirazinas/farmacocinética , Piridinas/farmacocinética , Trombina/antagonistas & inibidores , Acetamidas/síntese química , Acetamidas/farmacologia , Administração Oral , Animais , Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Macaca mulatta , Modelos Moleculares , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Introduction of a 5,6-dihydrouracil functionality in the 5-position of N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide 1 led to a series of highly active HIV-1 integrase inhibitors. These compounds displayed low nanomolar activity in inhibiting both the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 11 is a 150-fold more potent antiviral agent than 1, with a CIC(95) of 40 nM in the presence of human serum. It displays good pharmacokinetics when dosed in rats and dogs.
Assuntos
Compostos de Benzil/farmacologia , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Naftiridinas/farmacologia , Uracila/análogos & derivados , Replicação Viral/efeitos dos fármacos , Animais , Compostos de Benzil/química , Compostos de Benzil/farmacocinética , Disponibilidade Biológica , Cristalografia por Raios X , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacocinética , HIV-1/fisiologia , Naftiridinas/química , Naftiridinas/farmacocinética , Ratos , Uracila/químicaRESUMO
Modification of lead compound 1 by reducing lipophilicity in the P3 group produced a series of low molecular weight thrombin inhibitors with excellent potency in functional assays, metabolic stability, and oral bioavailability. These modifications led to the identification of two optimized compounds, 14 and 16.