RESUMO
The metabolism of our prototypical thrombin receptor antagonist 1, Ki = 2.7 nM, was studied and three major metabolites (2, 4, and 5) were found. The structures of the metabolites were verified independently by synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a Ki = 11 nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activity was sustained with 60% inhibition observed at 24 h post-dose. Compound 4 was highly active in functional assays and showed excellent oral bioavailability in rats and monkeys. Compound 4 showed a superior rat enzyme induction profile relative to compound 1, allowing it to replace compound 1 as a development candidate.
Assuntos
Furanos/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Inibidores da Agregação Plaquetária/síntese química , Piridinas/síntese química , Receptores de Trombina/antagonistas & inibidores , Animais , Disponibilidade Biológica , Sistema Enzimático do Citocromo P-450/biossíntese , Furanos/farmacocinética , Furanos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Técnicas In Vitro , Macaca fascicularis , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Structurally novel thrombin receptor (protease activated receptor 1, PAR-1) antagonists based on the natural product himbacine are described. The prototypical PAR-1 antagonist 55 showed a Ki of 2.7 nM in the binding assay, making it the most potent PAR-1 antagonist reported. 55 was highly active in several functional assays, showed excellent oral bioavailability in rat and monkey models, and showed complete inhibition of agonist-induced ex vivo platelet aggregation in cynomolgus monkeys after oral administration.
Assuntos
Alcaloides/síntese química , Fibrinolíticos/síntese química , Furanos/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Naftalenos/síntese química , Piperidinas/síntese química , Piridinas/síntese química , Receptor PAR-1/antagonistas & inibidores , Administração Oral , Alcaloides/química , Alcaloides/farmacologia , Animais , Disponibilidade Biológica , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Cromatografia Líquida de Alta Pressão , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Furanos/química , Furanos/farmacologia , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Técnicas In Vitro , Macaca fascicularis , Naftalenos/química , Naftalenos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Piridinas/química , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We have synthesized several C7-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound 5c from this series showed excellent PAR-1 activity (K i = 5.1 nM). We also present a model of these spirocyclic compounds docked to the PAR-1 receptor based on the X-ray crystal structure of vorapaxar bound to PAR-1 receptor. This model explains some of the structure-activity relationships in this series.
RESUMO
The structure-activity relationship (SAR) of the vinyl pyridine region of himbacine derived thrombin receptor (PAR-1) antagonists is described. A 2-vinylpyridyl ring substituted with an aryl or a heteroaryl group at the 5-position showed the best overall PAR-1 affinity and pharmacokinetic properties. One of the newly discovered analogs bearing a 5-(3-pyridyl) substituent showed excellent PAR-1 affinity (Ki = 22 nM) and oral activity with reduced ClogP and improved off-target selectivity compared to an earlier development candidate.
Assuntos
Alcaloides/química , Alcaloides/farmacologia , Furanos/química , Furanos/farmacologia , Naftalenos/química , Naftalenos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptor PAR-1/antagonistas & inibidores , Animais , Anticoagulantes/química , Anticoagulantes/farmacologia , Estrutura Molecular , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The synthesis and biological activity of a novel series of thrombin receptor antagonists is described. This series of compounds showed excellent in vitro and in vivo potency. The most potent compound 40 had an IC(50) of 7.6 nM and showed robust inhibition of platelet aggregation in a cynomolgus monkey model after oral administration.
Assuntos
Alcaloides/farmacologia , Química Farmacêutica/métodos , Furanos/farmacologia , Naftalenos/farmacologia , Parassimpatolíticos/farmacologia , Piperidinas/farmacologia , Receptores de Trombina/antagonistas & inibidores , Administração Oral , Alcaloides/química , Animais , Área Sob a Curva , Furanos/química , Concentração Inibidora 50 , Ligantes , Macaca fascicularis , Modelos Químicos , Naftalenos/química , Parassimpatolíticos/química , Piperidinas/química , Agregação Plaquetária/efeitos dos fármacos , Ligação Proteica , Ratos , Trombina/químicaRESUMO
The structure-activity relationship (SAR) of the lactone ring of himbacine derived thrombin receptor (PAR-1) antagonists (e.g., 2-5) is described. The effect of the lactone carbonyl group on binding to PAR-1 is dependent on the substitution pattern of the pyridine ring. A stereoselective intramolecular Michael addition reaction to the vinyl pyridine group was observed for these pyridine analogs of himbacine in basic conditions at elevated temperature.
Assuntos
Alcaloides/química , Furanos/química , Lactonas/química , Naftalenos/química , Piperidinas/química , Receptor PAR-1/antagonistas & inibidores , Concentração Inibidora 50 , Estrutura Molecular , Receptor PAR-1/metabolismo , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and SAR studies of a structurally novel series of highly potent thrombin receptor (PAR-1) antagonists are described. Compound 30 is a highly potent thrombin receptor antagonist (IC(50)=6.3 nM), a related compound 36 showing efficacy in a monkey ex vivo study.