Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia.

The orphan G-protein-coupled receptor GPR139 is highly expressed in the habenula, a small brain nucleus that has been linked to depression, schizophrenia (SCZ), and substance-use disorder. High-throughput screening and a medicinal chemistry structure-activity relationship strategy identified a novel series of potent and selective benzotriazinone-based GPR139 agonists. Herein, we describe the chemistry optimization that led to the discovery and validation of multiple potent and selective in vivo GPR139 agonist tool compounds, including our clinical candidate TAK-041, also known as NBI-1065846 (compound ).

First-Time Disclosure of CVN424, a Potent and Selective GPR6 Inverse Agonist for the Treatment of Parkinson's Disease: Discovery, Pharmacological Validation, and Identification of a Clinical Candidate.

Parkinson's disease (PD) is a chronic and progressive movement disorder with the urgent unmet need for efficient symptomatic therapies with fewer side effects. GPR6 is an orphan G-protein coupled receptor (GPCR) with highly restricted expression in dopamine receptor D2-type medium spiny neurons (MSNs) of the indirect pathway, a striatal brain circuit which shows aberrant hyperactivity in PD patients. Potent and selective GPR6 inverse agonists (IAG) were developed starting from a low-potency screening hit (EC = 43 μM).

In Vitro Biotransformation of the Nrf2 Activator Bardoxolone: Formation of an Epoxide Metabolite That Undergoes Two Novel Glutathione-Mediated Metabolic Pathways: Epoxide Reduction and Oxidative Elimination of Nitrile Moiety.

Metabolism of bardoxolone methyl (BARD-Me), an oleanolic acid derivative, and its epoxide metabolite was studied in different in vitro systems. BARD-Me also undergoes glutathione (GSH)-adduct formation via direct nucleophilic attack at the β-carbon of the α,β-unsaturated ketone substituent on the A-ring. The presence of an electron-withdrawing nitrile residue on the α-carbon increases the α,β-unsaturated ketone's susceptibility to nucleophilic attack by thiols.

Asymmetric synthesis of dihydroindanes by convergent alkoxide-directed metallacycle-mediated bond formation.

A convergent synthesis of highly substituted and stereodefined dihydroindanes is described from alkoxide-directed Ti-mediated cross-coupling of internal alkynes with substituted 4-hydroxy-1,6-enynes (substrates that derive from 2-directional functionalization of readily available epoxy alcohol derivatives). In addition to describing a new and highly stereoselective approach to bimolecular [2 + 2 + 2] annulation that delivers products not available with other methods in this area of chemical reactivity, evidence is provided to support annulation by way of regioselective alkyne-alkyne coupling, followed by metal-centered [4 + 2] rather than stepwise alkene insertion and reductive elimination. Overall, the reaction proceeds with exquisite stereochemical control and defines a convenient, convergent, and enantiospecific entry to fused carbocycles of great potential value in target-oriented synthesis and medicinal chemistry.

Metallacycle-Mediated Cross-Coupling with Substituted and Electronically Unactivated Alkenes.

This perspective surveys the history of- and recent advances in- metallacycle-mediated coupling chemistry of substituted alkenes. While the reaction of preformed metal-π complexes with ethylene was reported nearly 30 years ago, the generalization of this mode of bimolecular C-C bond formation to the regio- and stereoselective union of complex substrates has only recently begun to emerge. This perspective discusses early observations in this area, the challenges associated with controlling such processes, the evolution of a general strategy to overcome these challenges, and a summary of highly regio- and stereoselective convergent coupling reactions that are currently available by metallacycle-mediated cross-coupling with substituted alkenes.

Regioselective Reductive Cross-Coupling Reactions of Unsymmetrical Alkynes.

The present microreview summarizes our progress over the last few years in defining regioselective reductive cross-coupling reactions of unsymmetrical alkynes with terminal- and internal alkynes, aldehydes, and imines. We begin with a brief historical perspective of metal-mediated reductive dimerization reactions of aromatic alkynes and discuss the challenges associated with "crossed" versions of this mode of reactivity. Next, a collection of available methods that allow for regioselective reductive cross-coupling of internal alkynes with terminal and internal alkynes, aldehydes, and imines is summarized.