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1.
Bioorg Med Chem Lett ; 25(22): 5437-43, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26318999

RESUMO

Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Fator IXa/antagonistas & inibidores , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Administração Oral , Animais , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Compostos Heterocíclicos com 3 Anéis/síntese química , Humanos , Estrutura Molecular , Ratos
2.
ACS Med Chem Lett ; 6(8): 861-5, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288685

RESUMO

Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

3.
ACS Med Chem Lett ; 6(5): 573-8, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-26005536

RESUMO

We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

4.
Bioorg Med Chem Lett ; 23(12): 3650-3, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23659858

RESUMO

In an effort to understand the origin of blood-pressure lowering effects observed in recent clinical trials with 11ß-HSD1 inhibitors, we examined a set of 11ß-HSD1 inhibitors in a series of relevant in vitro and in vivo assays. Select 11ß-HSD1 inhibitors reduced blood pressure in our preclinical models but most or all of the blood pressure lowering may be mediated by a 11ß-HSD1 independent pathway.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Hipertensão/tratamento farmacológico , Hipertensão/enzimologia , Triazóis/farmacologia , Animais , Humanos , Camundongos , Camundongos Knockout , Ratos , Ratos Endogâmicos SHR
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