MARK inhibitors: Declaring a No-Go decision on a chemical series based on extensive DMPK experimentation. Issue 1 (1st January 2017)

• Record Type: Journal Article
• Authors: Haidle, Andrew M.; Childers, Kaleen K.; Zabierek, Anna A.; Katz, Jason D.; Jewell, James P.; Hou, Yongquan; Altman, Michael D.; Szewczak, Alexander; Chen, Dapeng; Harsch, Andreas; Hayashi, Mansuo; Warren, Lee; Hutton, Michael; Nuthall, Hugh; Stanton, Matt G.; Davies, Ian W.; Munoz, Ben; Northrup, Alan
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 1(2017)
• Page Start: 109
• Page End: 113
• Publication Date: 2017-01-01
• Subjects: MARK -- Kinase -- Pharmacokinetics -- Optimization -- Physical properties -- Disposition study -- In vitro–in vivo correlation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.08.066
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Attempts to optimize pharmacokinetic properties in a promising series of pyrrolopyrimidinone MARK inhibitors for the treatment of Alzheimer's disease are described. A focus on physical properties and ligand efficiency while prosecuting this series afforded key tool compounds that revealed a large discrepancy in the rat in vitro–in vivo DMPK (Drug Metabolism/Pharmacokinetics) correlation. These differences prompted an in vivo rat disposition study employing a radiolabeled representative of the series, and the results from this experiment justified the termination of any further optimization efforts.