RESUMO
A series of (6,7-dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines has been optimized to preserve both potent kinase inhibition activity against the angiogenesis target, the receptor tyrosine kinase of Platelet-Derived Growth Factor-BB (PDGF-BB), and to improve the broad tumor cell antiproliferative activity of these compounds. This series culminates in the discovery of 17 (JNJ-10198409), a compound with anti-PDGFR-beta kinase activity (IC(50)=0.0042 microM) and potent antiproliferative activity in six of eight human tumor cell lines (IC(50) < 0.033 microM).
Assuntos
Antineoplásicos/farmacologia , Indanos/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/síntese química , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Antineoplásicos/síntese química , Becaplermina , Linhagem Celular , Linhagem Celular Tumoral , Endotélio Vascular/efeitos dos fármacos , Humanos , Indanos/farmacologia , Concentração Inibidora 50 , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-sis , Pirazóis/farmacologiaRESUMO
[reaction: see text] Intramolecular Diels-Alder cycloaddition of tolylsulfonyl alkynone 5a and vinyl ketone 19 led to single isomers with opposite diastereoselectivity. Decalin 20 incorporates the correct C(9)-C(11) stereochemical array for a projected synthesis of HMP-Y1 (1).
