Abstract
A multidimensional, iterative parallel synthesis effort identified a series of highly selective mGlu3 NAMs with submicromolar potency and good CNS penetration. Of these, ML337 resulted (mGlu3 IC50 = 593 nM, mGlu2 IC50 >30 μM) 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%.
Original language | English |
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Pages (from-to) | 5208-5212 |
Number of pages | 5 |
Journal | Journal of Medicinal Chemistry |
Volume | 56 |
Issue number | 12 |
DOIs | |
State | Published - 27 Jun 2013 |