New class of azaheptapyridine FPT inhibitors as potential cancer therapy agents.

Zhu, Hugh Y; Desai, Jagdish; Cooper, Alan B; Wang, James; Rane, Dinananth F; Kirschmeier, Paul; Strickland, Corey; Liu, Ming; Nomeir, Amin A; Girijavallabhan, Viyyoor M

Zhu, Hugh Y; Desai, Jagdish; Cooper, Alan B; Wang, James; Rane, Dinananth F; Kirschmeier, Paul; Strickland, Corey; Liu, Ming; Nomeir, Amin A; Girijavallabhan, Viyyoor M.

Afiliação

Zhu HY; Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. Electronic address: hughzhu@hotmail.com.
Desai J; Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Cooper AB; Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Wang J; Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Rane DF; Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Kirschmeier P; Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Strickland C; Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Liu M; Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Nomeir AA; Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Girijavallabhan VM; Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.

Bioorg Med Chem Lett ; 24(4): 1228-31, 2014 Feb 15.

Article em En | MEDLINE | ID: mdl-24462667

ABSTRACT

ABSTRACT

Tertiary hydroxyl class of C-imidazole bridgehead azaheptapyridine FPT inhibitors were prepared in an attempt to block in vivo oxidation of secondary hydroxyl series. One representative compound 5a exhibited potent enzyme (IC50=1.4 nM) and cellular activities (soft agar IC50=1.3 nM) with excellent oral pharmacokinetic profiles in rats, mice, monkeys and dogs. The in vivo study in wap-ras TG mouse models showed dose dependent tumor growth inhibition and regression.

Assuntos

Alquil e Aril Transferases/antagonistas & inibidores; Antineoplásicos/farmacologia; Compostos Aza/farmacologia; Inibidores Enzimáticos/farmacologia; Neoplasias Experimentais/tratamento farmacológico; Piridinas/farmacologia; Alquil e Aril Transferases/metabolismo; Animais; Antineoplásicos/síntese química; Antineoplásicos/química; Compostos Aza/síntese química; Compostos Aza/química; Linhagem Celular Tumoral; Proliferação de Células/efeitos dos fármacos; Cristalografia por Raios X; Cães; Relação Dose-Resposta a Droga; Inibidores Enzimáticos/síntese química; Inibidores Enzimáticos/química; Haplorrinos; Humanos; Camundongos; Camundongos Transgênicos; Modelos Moleculares; Estrutura Molecular; Neoplasias Experimentais/patologia; Piridinas/síntese química; Piridinas/química; Ratos; Relação Estrutura-Atividade; Ensaios Antitumorais Modelo de Xenoenxerto

Palavras-chave

FPT inhibitors

Texto completo

Imprimir

XML

PubMed Links

Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piridinas / Compostos Aza / Alquil e Aril Transferases / Inibidores Enzimáticos / Neoplasias Experimentais / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2014 Tipo de documento: Article

Texto completo

Imprimir

XML

PubMed Links

Buscar no Google