Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy. Issue 12 (15th June 2016)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 12(2016)
• Page Start: 2915
• Page End: 2919
• Publication Date: 2016-06-15
• Subjects: mGlu4 -- Metabotropic glutamate receptor -- Positive allosteric modulator (PAM) -- Parkinson's disease -- Structure–activity relationship (SAR); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.04.041
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: This letter describes the further chemical optimization of the picolinamide-derived family of mGlu4 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) mGlu4 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).