Document Report Card

ID: ALA1157659

Journal: J Med Chem

Title: Design, synthesis, and biological evaluation of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent, orally active, brain penetrant inhibitor of phosphodiesterase 5 (PDE5).

Authors: Hughes RO, Rogier DJ, Jacobsen EJ, Walker JK, Macinnes A, Bond BR, Zhang LL, Yu Y, Zheng Y, Rumsey JM, Walgren JL, Curtiss SW, Fobian YM, Heasley SE, Cubbage JW, Moon JB, Brown DL, Acker BA, Maddux TM, Tollefson MB, Mischke BV, Owen DR, Freskos JN, Molyneaux JM, Benson AG, Blevis-Bal RM.

Abstract: We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.

CiteXplore: 20196613

DOI: 10.1021/jm901781q