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

作者：Gogliotti Rocco D; Engers Darren W; Garcia Barrantes Pedro M; Panarese Joseph D; Gentry Patrick R; Blobaum Anna L; Morrison Ryan D; Daniels J Scott; Thompson Analisa D; Jones Carrie K; Conn P Jeffrey; Niswender Colleen M; Lindsley Craig W^*; Hopkins Corey R^*

来源：Bioorganic & Medicinal Chemistry Letters, 2016, 26(12): 2915-2919.

DOI：10.1016/j.bmcl.2016.04.041

• mGlu(4)
• Metabotropic glutamate receptor
• Positive allosteric modulator (PAM)
• Parkinson's disease
• Structure-activity relationship (SAR)

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 (EC50 = 95 nM, 89% Glu Max) mGlu(4) PAM with an attractive DMPK profile (brain: plasma K-p = 1.3), rat CLp = 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).

• 出版日期2016-6-15