Reductions in log P improved protein binding and clearance predictions enabling the prospective design of cannabinoid receptor (CB1) antagonists with desired …

…, RB Sulsky, Z Gu, N Murugesan, Y Zhu…

Index: Ellsworth, Bruce A.; Sher, Philip M.; Wu, Ximao; Wu, Gang; Sulsky, Richard B.; Gu, Zhengxiang; Murugesan, Natesan; Zhu, Yeheng; Yu, Guixue; Sitkoff, Doree F.; Carlson, Kenneth E.; Kang, Liya; Yang, Yifan; Lee, Ning; Baska, Rose A.; Keim, William J.; Cullen, Mary Jane; Azzara, Anthony V.; Zuvich, Eva; Thomas, Michael A.; Rohrbach, Kenneth W.; Devenny, James J.; Godonis, Helen E.; Harvey, Susan J.; Murphy, Brian J.; Everlof, Gerry G.; Stetsko, Paul I.; Gudmundsson, Olafur; Johnghar, Susan; Ranasinghe, Asoka; Behnia, Kamelia; Pelleymounter, Mary Ann; Ewing, William R. Journal of Medicinal Chemistry, 2013 , vol. 56, # 23 p. 9586 - 9600

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Abstract

Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with< 5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely ...