Discovery, Structure–Activity Relationship, and Biological Characterization of a Novel Series of 6-((1H-Pyrazolo[4,3-b]pyridin-3-yl)amino)-benzo[d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu₄)

Abstract

This work describes the discovery and characterization of novel 6-(1Hpyrazolo[4,3-b]pyridin-3-yl)amino-benzo[d]isothiazole-3-carboxamides as mGlu 4 PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu 4 PAMs. From this work, 27o (VU6001376) was identified as a potent (EC 50 = 50.1 nM, 50.5% GluMax) and selective mGlu 4 PAM with an excellent rat DMPK profile (in vivo rat CL p = 3.1 mL/min/kg, t 1/2 = 445 min, CYP1A2 IC 50 > 30 μM). Compound 27o was also active in reversing haloperidol induced catalepsy in a rodent preclinical model of Parkinson's disease.

Haloperidol‐induced catalepsy as an animal model for parkinsonism: A systematic review of experimental studies

“…Atack et al, 2014;Trevitt et al, 2009;Wardas et al, 2003;Zheng et al, 2014); also, compounds that act as double A2A antagonist/MAO-B inhibitor demonstrated increased antiparkinsonian efficacy (Rivara et al, 2013;Wang et al, 2017). In the same direction, positive allosteric modulators of metabotropic glutamate receptor dose-dependently decreased haloperidol-induced catalepsy (e.g., Bollinger et al, 2019;Charvin et al, 2017;Niswender et al, 2008). Drugs used to treat other diseases have also been tested as potential therapeutic agents for parkinsonism in the catalepsy model.…”

New 1,2,4-oxadiazole derivatives with positive mGlu4 receptor modulation activity and antipsychotic-like properties

“…Similarly, the ligand (–)-PHCCC ( 3 , mGlu 4 EC 50 = 1.4 µM), originally thought to be a breakthrough, proved to be non-selective 20 , showing partial antagonist activity towards mGlu 1 receptor as well as agonist activity towards mGlu 6 34 . However, further pharmacological studies with the use of (–)–PHCCC ( 3 ) revealed its efficacy in animal models of Parkinson’s disease 7 , 20 , 33 , 35 , 38–44 , depression 45 , 46 , anxiety 47 , 48 , epilepsy 49 , 50 , neuroprotection 51 and oncology 52 but also showed a poor pharmacokinetic profile, limited brain exposure and low aqueous solubility 2 , 53 , 54 .…”

“…The reported PAMs of mGlu 4 receptor represent various chemical classes of compounds and different scaffolds 33 , such as picolinamides (e.g. VU0361737 ( 5 )) 9 , 15 , 31 , 58 , sulphonamides (e.g.…”

Discovery of VU2957 (Valiglurax): An mGlu4 Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson’s Disease

“…Selective activation of the metabotropic glutamate receptor subtype 4 (mGu 4 ), via either subtype selective agonists or positive allosteric modulators (PAMs), has been shown to decrease output of the indirect pathway in the basal ganglia and significantly reduce or eliminate motor symptoms in preclinical models of Parkinson’s disease (PD). − Other preclinical data with mGlu 4 PAMs suggest disease modification potential and that potentiation of mGlu 4 can be considered a “pharmacological mimic” of deep brain stimulation (DBS). − Recent data in DBS patients further strengthens the argument for mGlu 4 PAMs as a disease modifying, as well as a symptomatic, therapeutic approach. − A diverse array of mGlu 4 PAM chemotypes 1 – 5 have demonstrated preclinical efficacy in PD models (Figure ), but only recently has an mGlu 4 PAM (Prexton Therapeutics Foliglurax, 6 ) entered clinical development. , However, due to concerns with 6 (an α,β-unsaturated chromene oxime), efforts in the field continued to advance alternative mGlu 4 PAMs. In this Letter, we detail the discovery of a potent, selective (versus the other seven mGlu receptor subtypes, mGlu 1–3,5–8 ), and orally bioavailable mGlu 4 PAM (VU2957) from a novel scaffold that was evaluated as a preclinical candidate.…”

“…PAM 4 was our first compound to advance as a potential development candidate, but a CYP1A2 autoinduction liability prevented it from advancing into IND-enabling studies due to an inability to chronically administer the compound in vivo . , Further optimization of 4 led to several subseries of indazoles, benzo­[ d ]­isoxazoles, and benzo­[ d ]­isothiazoles (e.g., 3 ) as 5,6-heterobicyclic replacements for the halogenated phenyl ring of 4 , resulting in potent, CNS penetrant mGlu 4 PAMs wherein the CYP1A2 autoinduction liability was resolved by engendering a robust CYP metabolism phenotype and/or mitigating induction of CYP1A2 (Figure ). , However, these analogs, while displaying robust efficacy in preclinical PD models, did not possess profiles suitable as preclinical candidates due to solubility limited absorption, high projected human dose, and a small therapeutic window. Thus, we focused on 6,6-heterobicyclic systems and a 1-trifluormethyl isoquinoline-based PAM 7 (VU0652957, VU2957) emerged from the optimization effort as an mGlu 4 PAM worthy of in-depth profiling as a preclinical development candidate.…”