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 Kp = 1.3), rat CLp = 4.0 mL/min/kg, t1/2 = 3.7 h) and robust efficacy in our standard preclinical Parkinson's disease model, haloperidol-induced catalepsy (HIC).
Original language | English (US) |
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Pages (from-to) | 2915-2919 |
Number of pages | 5 |
Journal | Bioorganic and Medicinal Chemistry Letters |
Volume | 26 |
Issue number | 12 |
DOIs | |
State | Published - Jun 15 2016 |
Externally published | Yes |
Keywords
- Metabotropic glutamate receptor
- Parkinson's disease
- Positive allosteric modulator (PAM)
- Structure-activity relationship (SAR)
- mGlu
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry