Discovery of the First Potent and Orally Available Agonist of the Orphan G‑Protein-Coupled Receptor 52

G-protein-coupled receptor 52 (GPR52) is an orphan Gs-coupled G-protein-coupled receptor. GPR52 inhibits dopamine D₂ receptor signaling and activates dopamine D₁/<i>N</i>-methyl-d-aspartate receptors via intracellular cAMP accumulation, and therefore, GPR52 agonists may have potential as a novel class of antipsychotics. A series of GPR52 agonists with a bicyclic core was designed to fix the conformation of the phenethyl ether moiety of compounds <b>2a</b> and <b>2b</b>. 3-[2-(3-Chloro-5-fluorobenzyl)-1-benzothiophen-7-yl]-<i>N</i>-(2-methoxyethyl)­benzamide <b>7m</b> showed potent activity (pEC₅₀ = 7.53 ± 0.08) and good pharmacokinetic properties. Compound <b>7m</b> significantly suppressed methamphetamine-induced hyperactivity in mice after oral administration of 3 mg/kg without disturbance of motor function

Discovery of a Novel Pyrrole Derivative 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1<i>H</i>-pyrrol-3-yl]-<i>N</i>-methylmethanamine Fumarate (TAK-438) as a Potassium-Competitive Acid Blocker (P-CAB)

In our pursuit of developing a novel and potent potassium-competitive acid blocker (P-CAB), we synthesized pyrrole derivatives focusing on compounds with low log <i>D</i> and high ligand-lipophilicity efficiency (LLE) values. Among the compounds synthesized, the compound <b>13e</b> exhibited potent H⁺,K⁺-ATPase inhibitory activity and potent gastric acid secretion inhibitory action in vivo. Its maximum efficacy was more potent and its duration of action was much longer than those of proton pump inhibitors (PPIs). Therefore, compound <b>13e</b> (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1<i>H</i>-pyrrol-3-yl]-<i>N</i>-methylmethanamine fumarate, TAK-438) was selected as a drug candidate for the treatment of gastroesophageal reflux disease (GERD), peptic ulcer, and other acid-related diseases