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

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=95nM, 89% Glu Max) mGlu4 PAM with an attractive DMPK profile (brain:plasma Kp=1.3), rat CLp=4.0mL/min/kg, t1/2=3.7h) and robust efficacy in our standard preclinical Parkinson's disease model, haloperidol-induced catalepsy (HIC).

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Gogliotti RD,Engers DW,Garcia-Barrantes PM,Panarese JD,Gentry PR,Blobaum AL,Morrison RD,Daniels JS,Thompson AD,Jones CK,Conn PJ,Niswender CM,Lindsley CW,Hopkins CR

doi

10.1016/j.bmcl.2016.04.041

subject

Has Abstract

pub_date

2016-06-15 00:00:00

pages

2915-2919

issue

12

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(16)30414-0

journal_volume

26

pub_type

杂志文章

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