In vivo optimization of 2,3-diaminopyrazine Rho Kinase inhibitors for the treatment of glaucoma

abstract A series of 2,3,6-pyrazine Rho Kinase inhibitors were optimized for in vivo activity for topical ocular dos-ing. Modi“cations of the 2-(piperazin-1-yl)pyrazine derivatives produced compounds with improved sol-ubility and physicochemical properties. Modi“cations of the 6-pyrazine substituent led to improvementsin in vitro potency. Compound9 had the best in vitro and in vivo potency of EC 50 = 260 nM with a 30%reduction of IOP in a non-human primate model at a dose of 0.33%. 2014 Elsevier Ltd. All rights reserved. ROCK, Rho associated protein kinase is from the ACG familyof serine/threonine kinases. 1 ROCK exists in two isoforms ROCKI and ROCK II that are 65% homologous in amino acid sequenceand 92% homology in their kinase domain. 1 ROCK phosphory-lates Lim Kinase 1 (LIMK1) and Lim Kinase 2 (LIMK2) at con-served threonines in the activation loop increasing LIMKactivity. 1 ROCK also directly phosphorylates myosin light chain(MLC), and the myosin-binding subunit (MYPT1) of the myosinphosphatase to inhibit catalytic activity.