Discovery of (R)-(2-Fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-Hydroxypiperidin-1-yl)methanone (ML337), An mGlu(3) Selective and CNS Penetrant Negative Allosteric Modulator (NAM)

作者：Wenthur Cody J; Morrison Ryan; Felts Andrew S; Smith Katrina A; Engers Julie L; Byers Frank W; Daniels J Scott; Emmitte Kyle A; Conn P Jeffrey; Lindsley Craig W^*

来源：Journal of Medicinal Chemistry, 2013, 56(12): 5208-5212.

DOI：10.1021/jm400439t

A multidimensional, iterative parallel synthesis effort identified a series of highly selective mGlu(3) NAMs with submicromolar potency and good CNS penetration. Of these, ML337 resulted (mGlu(3) IC50 = 593 nM, mGlu(2) IC50 >30 mu M) with B:P ratios of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to the incorporation of deuterium atoms to address a metabolic soft spot, which subsequently lowered both in vitro and in vivo clearance by >50%.

• 出版日期2013-6-27