RESUMO
In an effort to prepare orally bioavailable analogs of our previously reported thrombin inhibitor 1, we have synthesized a series of compounds that utilize the unique amino acid D-dicyclohexylalanine as a P3 ligand. The resulting compounds are extremely potent and selective thrombin inhibitors, and the N-terminal Boc derivative 8 exhibited excellent oral bioavailability and pharmacokinetics in both rats and dogs. The des-Boc analog 6 was not orally bioavailable in rats. The high level of oral bioavailability observed with 8 appears to be a direct function of its increased lipophilicity versus other close analogs. Although increased lipophilicity may serve to increase the oral absorption of tripeptide thrombin inhibitors, it also appears to have detrimental effects on the antithrombotic properties observed with the compounds. Compound 6 performed extremely well in our in vivo antithrombotic assay, while the much more lipophilic but essentially equipotent analog 8 performed poorly. We have found that in general with this series of thrombin inhibitors as well as with other unreported series, increased lipophilicity and the associated increases in plasma protein binding have detrimental effects on 2X APTT values and subsequent performance in in vivo antithrombotic models.
Assuntos
Dipeptídeos/síntese química , Fibrinolíticos/síntese química , Fenilalanina/análogos & derivados , Trombina/antagonistas & inibidores , Animais , Disponibilidade Biológica , Dipeptídeos/farmacocinética , Dipeptídeos/uso terapêutico , Cães , Fibrinolíticos/farmacocinética , Fibrinolíticos/uso terapêutico , Metabolismo dos Lipídeos , Masculino , Estrutura Molecular , Tempo de Tromboplastina Parcial , Fenilalanina/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Trombose/tratamento farmacológicoRESUMO
A novel class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position has been discovered. Four of these thrombin inhibitors (13b,c,e and 14d) showed nanomolar potency (Ki 0.8-12 nM), 300-1500-fold selectivity for thrombin compared with trypsin, and good oral bioavailability (F = 40-76%) in rats or dogs. The neutral P1 was expected to increase metabolic stability and oral absorption. Identification of this novel aminopyridyl group at P1 was a key step in our search for a clinical candidate.
Assuntos
Antitrombinas/síntese química , Antitrombinas/farmacologia , Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Trombina/antagonistas & inibidores , Administração Oral , Animais , Antitrombinas/farmacocinética , Disponibilidade Biológica , Cristalografia por Raios X , Dipeptídeos/farmacocinética , Cães , Cinética , Piridinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Trombina/metabolismoRESUMO
As part of an effort to prepare efficacious and orally bioavailable analogs of the previously reported thrombin inhibitors 1a, b, we have synthesized a series of compounds that utilize 3,3-disubstituted propionic acid derivatives as P3 ligands. By removing the N-terminal amino group, the general oral bioavailability of this class of compounds was enhanced without excessively increasing the lipophilicity of the compounds. The overall properties of the molecules could be drastically altered depending on the nature of the groups substituted onto the 3-position of the P3 propionic acid moiety. A number of the compounds exhibited good oral bioavailability in rats and dogs, and numerous compounds were efficacious in a rat FeCl3-induced model of arterial thrombosis. Compound 7, the 3,3-diphenylpropionic acid derivative, showed the best overall profile of in vivo and in vitro activity. Molecular modeling studies suggest that these compounds bind in the thrombin active site in a manner essentially identical to that previously reported for compound 1a.
Assuntos
Propionatos/síntese química , Trombina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Cães , Espectroscopia de Ressonância Magnética , Propionatos/farmacocinética , Propionatos/farmacologia , Ratos , Espectrometria de Massas de Bombardeamento Rápido de ÁtomosRESUMO
As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.
Assuntos
Cicloexilaminas/síntese química , Dipeptídeos/síntese química , Fibrinolíticos/síntese química , Trombina/antagonistas & inibidores , Administração Oral , Animais , Sítios de Ligação , Disponibilidade Biológica , Simulação por Computador , Cristalografia por Raios X , Cicloexilaminas/química , Cicloexilaminas/farmacocinética , Dipeptídeos/química , Dipeptídeos/farmacocinética , Cães , Desenho de Fármacos , Fibrinolíticos/química , Fibrinolíticos/farmacocinética , Fibrinolíticos/farmacologia , Ligação de Hidrogênio , Macaca fascicularis , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Ratos , Resinas Vegetais , Relação Estrutura-Atividade , Trombina/químicaRESUMO
Novel potent and selective diarylimidazole inhibitors of p38 MAP (mitogen-activated protein) kinase are described which have activity in both cell-based assays of tumor necrosis factor-alpha (TNF-alpha) release and an animal model of rheumatoid arthritis. The SAR leading to the development of selectivity against c-Raf and JNK2alpha1 kinases is presented, with key features being substitution of the 4-aryl ring with m-trifluoromethyl and substitution of the 5-heteroaryl ring with a 2-amino substituent. Cell-based activity was significantly enhanced by incorporation of a 4-piperidinyl moiety at the 2-position of the imidazole which also enhanced aqueous solubility. In general, oral bioavailability of this class of compounds was found to be poor unless the imidazole was methylated on nitrogen. This work led to identification of 48, a potent (p38 MAP kinase inhibition IC50 0.24 nM) and selective p38 MAP kinase inhibitor which inhibits lipopolysaccharide-stimulated release of TNF-alpha from human blood with an IC50 2.2 nM, shows good oral bioavailability in rat and rhesus monkey, and demonstrates significant improvement in measures of disease progression in a rat adjuvant-induced arthritis model.