A General Protocol for the Broad-Spectrum Cross-Coupling of Nonactivated Sterically Hindered 1° and 2° Amines

While notable advances have been reported for the metal-catalyzed cross-coupling of bulky amines, to date no set of reported conditions has proven general for both hindered and unactivated primary and secondary amines. Examples that are reported with Pd catalysts invariably involve aggressive alkoxide bases in order to provide the necessary “push” required to couple these challenging substrates. Consequently, few, if any, base-sensitive functional groups (e.g., esters, ketones, cyano groups) are included in published reports involving such substrates. Herein we disclose the use of <i>Pd-PEPPSI-IPent</i>^<i>Cl</i><i>3-chloropyridine</i> precatalyst with the mild, yet soluble base sodium butylated hydroxytoluene (NaBHT) in one single protocol that can couple a broad scope of hindered and unactivated primary and secondary amines to produce functionalized products in high yields

Discovery, Structure–Activity Relationship, and Antiparkinsonian Effect of a Potent and Brain-Penetrant Chemical Series of Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4

The metabotropic glutamate receptor 4 (mGluR4) is an emerging target for the treatment of Parkinson’s disease (PD). However, since the discovery of its therapeutic potential, no ligand has been successfully developed enough to be tested in the clinic. In the present paper, we report for the first time the medicinal chemistry efforts conducted around the pharmacological tool (−)-PHCCC. This work led to the identification of compound <b>40</b>, a potent and selective mGluR4 positive allosteric modulator (PAM) with good water solubility and demonstrating consistent activity across validated preclinical rodent models of PD motor symptoms after intraperitoneal administration: haloperidol-induced catalepsy in mouse and the rat 6-hydroxydopamine (6-OHDA) lesion model. Moreover, we also describe the identification of compound <b>60</b> a close analogue of compound <b>40</b> with improved pharmacokinetic profile after oral administration. On the basis of its favorable and unique preclinical profile, compound <b>60</b> (PXT002331, now foliglurax) was nominated as a candidate for clinical development

Discovery, Structure–Activity Relationship, and Antiparkinsonian Effect of a Potent and Brain-Penetrant Chemical Series of Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4

The metabotropic glutamate receptor 4 (mGluR4) is an emerging target for the treatment of Parkinson’s disease (PD). However, since the discovery of its therapeutic potential, no ligand has been successfully developed enough to be tested in the clinic. In the present paper, we report for the first time the medicinal chemistry efforts conducted around the pharmacological tool (−)-PHCCC. This work led to the identification of compound <b>40</b>, a potent and selective mGluR4 positive allosteric modulator (PAM) with good water solubility and demonstrating consistent activity across validated preclinical rodent models of PD motor symptoms after intraperitoneal administration: haloperidol-induced catalepsy in mouse and the rat 6-hydroxydopamine (6-OHDA) lesion model. Moreover, we also describe the identification of compound <b>60</b> a close analogue of compound <b>40</b> with improved pharmacokinetic profile after oral administration. On the basis of its favorable and unique preclinical profile, compound <b>60</b> (PXT002331, now foliglurax) was nominated as a candidate for clinical development