Discovery of (<i>R</i>)‑(2-Fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-Hydroxypiperidin-1-yl)methanone (ML337), An mGlu₃ Selective and CNS Penetrant Negative Allosteric Modulator (NAM)

A multidimensional, iterative parallel synthesis effort identified a series of highly selective mGlu₃ NAMs with submicromolar potency and good CNS penetration. Of these, ML337 resulted (mGlu₃ IC₅₀ = 593 nM, mGlu₂ IC₅₀ >30 μM) with B:P ratios of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to the incorporation of deuterium atoms to address a metabolic soft spot, which subsequently lowered both in vitro and in vivo clearance by >50%

Discovery, Synthesis, and Preclinical Characterization of <i>N</i>‑(3-Chloro-4-fluorophenyl)‑1<i>H</i>‑pyrazolo[4,3‑<i>b</i>]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu₄)

The efficacy of positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 4 (mGlu₄) in preclinical rodent models of Parkinson’s disease has been established by a number of groups. Here, we report an advanced preclinically characterized mGlu₄ PAM, <i>N</i>-(3-chloro-4-fluorophenyl)-1<i>H</i>-pyrazolo­[4,3-<i>b</i>]­pyridin-3-amine (VU0418506). We detail the discovery of VU0418506 starting from a common picolinamide core scaffold and evaluation of a number of amide bioisosteres leading to the novel pyrazolo­[4,3-<i>b</i>]­pyridine head group. VU0418506 has been characterized as a potent and selective mGlu₄ PAM with suitable in vivo pharmacokinetic properties in three preclinical safety species

Discovery, Synthesis, and Structure–Activity Relationship Development of a Series of <i>N</i>-4-(2,5-Dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): Characterization of a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu₄) with Oral Efficacy in an Antiparkinsonian Animal Model

There is an increasing amount of literature data showing the positive effects on preclinical antiparkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu₄). However, most of the data generated utilize compounds that have not been optimized for druglike properties, and as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood–brain barrier. Herein, we report on a series of <i>N</i>-4-(2,5-dioxopyrrolidin-1-yl)­phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established antiparkinsonian model