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1.
Bioorg Med Chem Lett ; 26(2): 575-579, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26675441

RESUMO

BTK inhibitor GDC-0834 (1) was found to be rapidly metabolized in human studies, resulting in a suspension of clinical trials. The primary route of metabolism was through cleavage of the acyclic amide bond connecting the terminal tetrahydrobenzothiophene with the central linker aryl ring. SAR studies were focused on reducing metabolic cleavage of this amide, and resulted in the identification of several central aryl linker substituents that conferred improved stability. The most promising substituted aryl linkers were then incorporated into an optimized pyridazinone scaffold, resulting in the identification of lead analog 23, possessing improved potency, metabolic stability and preclinical properties.


Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridazinas/química , Piridazinas/farmacologia , Pirimidinonas/química , Pirimidinonas/farmacologia , Tiofenos/química , Tiofenos/farmacologia , Tirosina Quinase da Agamaglobulinemia , Animais , Cães , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/metabolismo , Piridazinas/metabolismo , Piridazinas/farmacocinética , Pirimidinonas/metabolismo , Pirimidinonas/farmacocinética , Ratos , Tiofenos/metabolismo , Tiofenos/farmacocinética
2.
Bioorg Med Chem Lett ; 25(6): 1333-7, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25701252

RESUMO

SAR studies focused on improving the pharmacokinetic (PK) properties of the previously reported potent and selective Btk inhibitor CGI-1746 (1) resulted in the clinical candidate GDC-0834 (2), which retained the potency and selectivity of CGI-1746, but with much improved PK in preclinical animal models. Structure based design efforts drove this work as modifications to 1 were investigated at both the solvent exposed region as well as 'H3 binding pocket'. However, in vitro metabolic evaluation of 2 revealed a non CYP-mediated metabolic process that was more prevalent in human than preclinical species (mouse, rat, dog, cyno), leading to a high-level of uncertainly in predicting human pharmacokinetics. Due to its promising potency, selectivity, and preclinical efficacy, a single dose IND was filed and 2 was taken in to a single dose phase I trial in healthy volunteers to quickly evaluate the human pharmacokinetics. In human, 2 was found to be highly labile at the exo-cyclic amide bond that links the tetrahydrobenzothiophene moiety to the central aniline ring, resulting in insufficient parent drug exposure. This information informed the back-up program and discovery of improved inhibitors.


Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinonas/química , Tiofenos/química , Tirosina Quinase da Agamaglobulinemia , Animais , Benzamidas/química , Benzamidas/metabolismo , Sítios de Ligação , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Cristalografia por Raios X , Cães , Meia-Vida , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/metabolismo , Pirimidinonas/síntese química , Pirimidinonas/farmacocinética , Ratos , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/farmacocinética
3.
ACS Med Chem Lett ; 8(6): 608-613, 2017 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-28626519

RESUMO

In our continued effort to discover and develop best-in-class Bruton's tyrosine kinase (Btk) inhibitors for the treatment of B-cell lymphomas, rheumatoid arthritis, and systemic lupus erythematosus, we devised a series of novel tricyclic compounds that improved upon the druglike properties of our previous chemical matter. Compounds exemplified by G-744 are highly potent, selective for Btk, metabolically stable, well tolerated, and efficacious in an animal model of arthritis.

4.
J Med Chem ; 57(9): 3856-73, 2014 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-24779514

RESUMO

Spleen tyrosine kinase (Syk) is an attractive drug target in autoimmune, inflammatory, and oncology disease indications. The most advanced Syk inhibitor, R406, 1 (or its prodrug form fostamatinib, 2), has shown efficacy in multiple therapeutic indications, but its clinical progress has been hampered by dose-limiting adverse effects that have been attributed, at least in part, to the off-target activities of 1. It is expected that a more selective Syk inhibitor would provide a greater therapeutic window. Herein we report the discovery and optimization of a novel series of imidazo[1,2-a]pyrazine Syk inhibitors. This work culminated in the identification of GS-9973, 68, a highly selective and orally efficacious Syk inhibitor which is currently undergoing clinical evaluation for autoimmune and oncology indications.


Assuntos
Indazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazinas/farmacologia , Baço/efeitos dos fármacos , Administração Oral , Animais , Células Cultivadas , Descoberta de Drogas , Humanos , Indazóis/administração & dosagem , Indazóis/química , Espectroscopia de Ressonância Magnética , Camundongos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Pirazinas/administração & dosagem , Pirazinas/química , Ratos , Espectrometria de Massas por Ionização por Electrospray , Baço/enzimologia , Relação Estrutura-Atividade
5.
Alcohol Clin Exp Res ; 27(8): 1327-9, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12966331

RESUMO

There has been an increasing call for and development of culturally appropriate substance prevention/intervention for ethnic minorities in schools and communities, especially among reservation and in urban American Indian and Alaska Native (AIAN) communities. Past attempts to intervene in and reduce misuse of alcohol and other drugs have not had great success. The Journeys of the Circle Project utilized innovative programs with a strong emphasis on historic cultural traditions.


Assuntos
Adaptação Psicológica , Consumo de Bebidas Alcoólicas/etnologia , Consumo de Bebidas Alcoólicas/prevenção & controle , Indígenas Norte-Americanos , Adolescente , Humanos , Fatores de Risco , Estados Unidos
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