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 Novel, Highly Potent, and Selective Matrix Metalloproteinase (MMP)-13 Inhibitors with a 1,2,4-Triazol-3-yl Moiety as a Zinc Binding Group Using a Structure-Based Design Approach

On the basis of a superposition study of X-ray crystal structures of complexes of quinazoline derivative <b>1</b> and triazole derivative <b>2</b> with matrix metalloproteinase (MMP)-13 catalytic domain, a novel series of fused pyrimidine compounds which possess a 1,2,4-triazol-3-yl group as a zinc binding group (ZBG) was designed. Among the herein described and evaluated compounds, <b>31f</b> exhibited excellent potency for MMP-13 (IC₅₀ = 0.036 nM) and selectivities (greater than 1,500-fold) over other MMPs (MMP-1, -2, -3, -7, -8, -9, -10, and -14) and tumor necrosis factor-α converting enzyme (TACE). Furthermore, the inhibitor was shown to protect bovine nasal cartilage explants against degradation induced by interleukin-1 and oncostatin M. In this article, we report the discovery of extremely potent, highly selective, and orally bioavailable fused pyrimidine derivatives that possess a 1,2,4-triazol-3-yl group as a novel ZBG for selective MMP-13 inhibition

Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists

Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF₁) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF₁ receptor antagonists. In a structure–activity relationship study, 4-chloro-<i>N</i>²-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-<i>N</i>⁷,<i>N</i>⁷-dipropyl-1<i>H</i>-benzimidazole-2,7-diamine <b>29g</b> had the most potent binding activity against a human CRF₁ receptor and the antagonistic activity (IC₅₀ = 9.5 and 88 nM, respectively) without concerns regarding cytotoxicity at 30 μM. Potent CRF₁ receptor-binding activity in brain in an ex vivo test and suppression of stress-induced activation of the hypothalamus–pituitary–adrenocortical (HPA) axis were also observed at 138 μmol/kg of compound <b>29g</b> after oral administration in mice. Thus, the newly designed benzimidazole <b>29g</b> showed in vivo CRF₁ receptor antagonistic activity and good brain penetration, indicating that it is a promising lead for CRF₁ receptor antagonist drug discovery research

Optimization of (2,3-Dihydro-1-benzofuran-3-yl)acetic Acids: Discovery of a Non-Free Fatty Acid-Like, Highly Bioavailable G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonist as a Glucose-Dependent Insulinotropic Agent

G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) is a free fatty acid (FFA) receptor that mediates FFA-amplified glucose-stimulated insulin secretion in pancreatic β-cells. We previously identified (2,3-dihydro-1-benzofuran-3-yl)­acetic acid derivative <b>2</b> as a candidate, but it had relatively high lipophilicity. Adding a polar functional group on <b>2</b> yielded several compounds with lower lipophilicity and little effect on caspase-3/7 activity at 30 μM (a marker of toxicity in human HepG2 hepatocytes). Three optimized compounds showed promising pharmacokinetic profiles with good in vivo effects. Of these, compound <b>16</b> had the lowest lipophilicity. Metabolic analysis of <b>16</b> showed a long-acting PK profile due to high resistance to β-oxidation. Oral administration of <b>16</b> significantly reduced plasma glucose excursion and increased insulin secretion during an OGTT in type 2 diabetic rats. Compound <b>16</b> (TAK-875) is being evaluated in human clinical trials for the treatment of type 2 diabetes