RESUMO
The N,N'-disubstituted cyanoguanidine is an excellent bioisostere of the thiourea and ketene aminal functional groups. We report the design and synthesis of a novel class of cyanoguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The SAR studies led to the discovery of compound 4 (BMS-269223, K(i)=6.5nM, EC(2xPT)=32muM) as a selective, orally bioavailable FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. The X-ray crystal structure of 4 bound in FXa is presented and key ligand-protein interactions are discussed.
Assuntos
Antitrombina III/farmacologia , Benzofuranos/farmacologia , Guanidinas/química , Lactamas/química , Administração Oral , Animais , Antitrombina III/química , Benzofuranos/química , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Cães , Haplorrinos , Humanos , Concentração Inibidora 50 , Cinética , Lactamas/farmacologia , Ligantes , Modelos Químicos , Ratos , Relação Estrutura-Atividade , Tioureia/químicaRESUMO
We report the design and synthesis of a novel class of N,N'-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC(50)=4 nM, EC(2xPT)=7 microM). However, the potent CYP3A4 inhibition activity (IC(50)=0.3 microM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC(50)=9 nM, EC(2xPT)=2.5 microM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.
Assuntos
Anticoagulantes/química , Inibidores do Fator Xa , Guanidinas/química , Inibidores de Serina Proteinase/química , Anticoagulantes/farmacologia , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Descoberta de Drogas , Guanidinas/farmacologia , Humanos , Concentração Inibidora 50 , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-AtividadeRESUMO
Synthesis and SAR of substituted pyrrolotriazine-4-one analogues as Eg5 inhibitors are described. Many of these analogues displayed potent inhibitory activities in the Eg5 ATPase and A2780 cell proliferation assays. In addition, pyrrolotriazine-4-one analogue 26 demonstrated in vivo efficacy in an iv P388 murine leukemia model. Both NMR and X-ray crystallographic studies revealed that these analogues bind to an allosteric site on the Eg5 protein.
Assuntos
Cinesinas/antagonistas & inibidores , Pirróis/síntese química , Pirróis/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Pirróis/química , Relação Estrutura-AtividadeRESUMO
Computer aided drug design led to a new class of spiro-barbiturates (e.g., 4a, MMP-13 K(i)=4.7 nM) that are potent inhibitors of MMP-13.
Assuntos
Barbitúricos/síntese química , Inibidores Enzimáticos/química , Inibidores de Metaloproteinases de Matriz , Barbitúricos/farmacologia , Simulação por Computador , Desenho Assistido por Computador , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Cinética , Metaloproteinase 13 da Matriz , Modelos Moleculares , Osteoartrite/tratamento farmacológico , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
N,N'-Disubstituted ketene aminals are good bioisosteres of thiourea functional groups. We report the design and synthesis of a novel class of ketene aminal-based lactam derivatives as potent and orally active FXa inhibitors.
Assuntos
Etilenos/farmacologia , Inibidores do Fator Xa , Cetonas/farmacologia , Lactamas/farmacologia , Administração Oral , Etilenos/administração & dosagem , Etilenos/química , Humanos , Cetonas/administração & dosagem , Cetonas/química , Lactamas/administração & dosagem , Modelos Moleculares , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
A series of benzodiazepine-based inhibitors of mitochondrial F(1)F(0) ATP hydrolase were prepared and evaluated for their ability to selectively inhibit the enzyme in the forward direction. Compounds from this series showed excellent potency and selectivity for ATP hydrolase versus ATP synthase, suggesting a potentially beneficial profile useful for the treatment of ischemic heart disease.