RESUMO
The evaluation of a series of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines as inhibitors of the IGF-1R (IGF-IR) receptor tyrosine kinase is reported. Examples demonstrate nanomolar potencies in in vitro enzyme and mechanistic cellular assays as well as promising in vivo pharmacokinetics in rat.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Descoberta de Drogas , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/química , RatosRESUMO
Initial evaluation of a series 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines revealed a C(1') carboxamide was preferred for sub-micromolar in vitro potency against IGF-1R. Subsequent solution stability studies with 1 revealed a susceptibility toward acid-induced intramolecular cyclization with the C(1') carboxamide. Herein, we describe several successful approaches toward generating both potent and acid-stable inhibitors of IGF-1R within the 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine template.
Assuntos
Ácidos/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Pirróis/químicaRESUMO
The SAR of C5' functional groups with terminal basic amines at the C6 aniline of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines is reported. Examples demonstrate potent inhibition of IGF-1R with 1000-fold selectivity over JNK1 and 3 in enzymatic assays.
Assuntos
MAP Quinase Quinase 4/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Modelos Moleculares , Pirimidinas/química , Pirróis/química , Relação Estrutura-AtividadeRESUMO
A synthetic route to bisanilino-1H-pyrrolo[2,3-d]pyrimidines has been discovered, wherein the C(6)-chloride reactivity is necessarily enhanced via reversible acid-catalyzed internal activation of the pyrimidine ring by a C(1')-carboxamide moiety. Subsequent selective nucleophilic displacements at C(6) and C(1') constitute a one-pot tandem protocol for the rapid assembly of bisanilino-1H-pyrrolo[2,3-d]pyrimidines.
Assuntos
Amidas/química , Química Orgânica/métodos , Pirimidinas/química , Pirróis/química , Carbono/química , Catálise , Cloretos/química , Desenho de Fármacos , Modelos QuímicosRESUMO
A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17beta-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was selected as the lead candidate.
Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Tiofenos/química , Tiofenos/farmacologia , 17-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Linhagem Celular , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Macaca fascicularis , Pirrolidinonas/síntese química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/síntese químicaRESUMO
4,5-Disubstituted cis-pyrrolidinones were investigated as inhibitors of type II 17beta-hydroxysteroid dehydrogenase (17beta-HSD). Early structure-activity relationship patterns for this class of compounds are discussed.
Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Pirrolidinonas/farmacologia , 17-Hidroxiesteroide Desidrogenases/metabolismo , Inibidores Enzimáticos/química , Humanos , Pirrolidinonas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Inhibitors of the MAP kinase p38 provide a novel approach for the treatment of osteoporosis, inflammatory disorders, and cancer. We have identified N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea as a potent and selective p38 kinase inhibitor in biochemical and cellular assays. This compound is orally active in two acute models of cytokine release (TNF-induced IL-6 and LPS-induced TNF) and a chronic model of arthritis (20-day murine collagen-induced arthritis).
