Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy.

This letter describes the further chemical optimization of the picolinamide-derived family of mGlu 4 PAMs wherein we identified a 3-amino substituent to the picolinamide warhead that engendered potency, CNS penetration and in vivo efficacy. From this optimization campaign, VU0477886 emerged as a potent (EC 50 = 95 nM, 89% Glu Max) mGlu 4 PAM with an attractive DMPK profile (brain:plasma K p = 1.3), rat CL p = 4.0 mL/min/kg, t 1/2 = 3.7 h) and robust efficacy in our standard preclinical Parkinson’s disease model, haloperidol-induced catalepsy (HIC). [ABSTRACT FROM AUTHOR]