RESUMO
A new set of quinazolinedione sulfonamide derivatives as competitive AMPA receptor antagonist with improved properties compared to 1 is disclosed. By modulating physico-chemical properties, compound 29 was identified with a low ED(50) of 5.5mg/kg in an animal model of anticonvulsant activity after oral dosage.
Assuntos
Anticonvulsivantes/farmacologia , Quinazolinonas/farmacologia , Receptores de AMPA/antagonistas & inibidores , Sulfonamidas/farmacologia , Administração Oral , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/química , Cristalografia por Raios X , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos DBA , Modelos Moleculares , Estrutura Molecular , Quinazolinonas/administração & dosagem , Quinazolinonas/química , Convulsões/tratamento farmacológico , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/químicaRESUMO
The action of renin is the rate-limiting step of the renin-angiotensin system (RAS), a key regulator of blood pressure. Effective renin inhibitors directly block the RAS entirely at source and, thus, may provide a vital weapon for hypertension therapy. Our efforts toward identifying novel small-molecule peptidomimetic renin inhibitors have resulted in the design of transition-state isosteres such as 1 bearing an all-carbon 8-phenyl-octanecarboxamide framework. Optimization of the extended P3 portion of 1 and extensive P2' modifications provided analogues with improved in vitro potencies in the presence of plasma. X-ray resolution of rh-renin/38a in the course of SAR work surprisingly unveiled the exploitation of a previously unexplored pocket (S3sp) important for strong binding affinities. Several inhibitors demonstrated oral efficacy in sodium-depleted marmosets. The most potent, 38a, induced dose-dependently a pronounced reduction in mean arterial blood pressure, paralleled by complete blockade of active plasma renin, up to 8 h post-dose. Oral bioavailability of 38a was 16% in marmosets.
Assuntos
Amidas/síntese química , Anisóis/síntese química , Anti-Hipertensivos/síntese química , Caprilatos/síntese química , Peptídeos/química , Renina/antagonistas & inibidores , Administração Oral , Amidas/química , Amidas/farmacologia , Animais , Anisóis/química , Anisóis/farmacologia , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Disponibilidade Biológica , Pressão Sanguínea/efeitos dos fármacos , Callithrix , Caprilatos/química , Caprilatos/farmacologia , Cristalografia por Raios X , Frequência Cardíaca/efeitos dos fármacos , Humanos , Cinética , Modelos Moleculares , Mimetismo Molecular , Estrutura Molecular , Ligação Proteica , Renina/sangue , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, and heart failure, the leading causes of death in the Western world. Inhibitors of the renin-angiotensin system (RAS) have proven to be successful treatments for hypertension. As renin specifically catalyses the rate-limiting step of the RAS, it represents the optimal target for RAS inhibition. Several peptide-like renin inhibitors have been synthesized previously, but poor pharmacokinetic properties meant that these compounds were not clinically useful. We employed a combination of molecular modelling and crystallographic structure analysis to design renin inhibitors lacking the extended peptide-like backbone of earlier inhibitors, for improved pharmacokinetic properties. This led to the discovery of aliskiren, a highly potent and selective inhibitor of human renin in vitro, and in vivo; once-daily oral doses of aliskiren inhibit renin and lower blood pressure in sodium-depleted marmosets and hypertensive human patients. Aliskiren represents the first in a novel class of renin inhibitors with the potential for treatment of hypertension and related cardiovascular diseases.