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[Display omitted] Motilin is a 22-amino-acid gastrointestinal (GI) hormone and is involved in the regulation of GI motility through binding to GPR38, the motilin receptor which is expressed on smooth muscle cells in the GI tract. Therefore, GPR38 agonists are expected to be novel gastrointestinal prokinetic agents for the treatment of functional gastrointestinal disorders such as gastroparesis and chronic constipation. We identified a series of N -methylanilide derivatives as novel non-macrolide GPR38 agonists. Among them, 12 di- l -tartrate (DS-3801b) was selected as a clinical candidate for further evaluation. [ABSTRACT FROM AUTHOR]

Abstract: An efficient methodology for the synthesis of 2,2,3-trisubstituted tetrahydroquinolines has been developed, which involves the triphenylphosphine–CCl4-mediated stereospecific rearrangement of α,α-disubstituted indoline-2-methanols 15 to 2,2,3-trisubstituted tetrahydroquinolines 26. The rearrangement precursors 15 are readily prepared by the diastereoselective Grignard addition to 2-acylindolines 13. The total syntheses of (+)-benzastatin E (1) and natural virantmycin (2a) were accomplished utilizing this methodology. This rearrangement reaction might afford some chemical precedent for the biogenetic pathway of the benzastatin family. [Copyright &y& Elsevier]

Alzheimer''s disease (AD) has been treated with acetylcholinesterase (AChE) inhibitors such as donepezil. However, the clinical usefulness of AChE inhibitors is limited mainly due to their adverse peripheral effects. Depression seen in AD patients has been treated with serotonin transporter (SERT) inhibitors. We considered that combining SERT and AChE inhibition could improve the clinical usefulness of AChE inhibitors. In a previous paper, we found a potential dual inhibitor, 1, of AChE (IC50=101 nM) and SERT (IC50=42 nM), but its AChE inhibition activity was less than donepezil (IC50=10 nM). Here, we report the conformationally restricted (R)-18a considerably enhanced inhibitory activity against AChE (IC50=14 nM) and SERT (IC50=6 nM). [Copyright &y& Elsevier]

We have designed and synthesized a dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT) as a novel class of treatment drugs for Alzheimer''s disease on the basis of a hypothetical model of the AChE active site. Dual inhibitions of AChE and SERT would bring about greater therapeutic effects than AChE inhibition alone and avoid adverse peripheral effects caused by excessive AChE inhibition. Compound (S)-6j exhibited potent inhibitory activities against AChE (IC50=101 nM) and SERT (IC50=42 nM). Furthermore, (S)-6j showed inhibitory activities of both AChE and SERT in mice brain following oral administration. [Copyright &y& Elsevier]

GPR40 agonists stimulate insulin secretion only under the presence of high glucose concentration. Based on this mechanism, GPR40 agonists are believed to be promising novel insulin secretagogues with low risk of hypoglycemia. The optimizations of 3-aryl-3-ethoxypropanoic acids were performed to improve in vitro activity. We discovered compound 29r (DS-1558), (3 S )-3-ethoxy-3-(4-{[(1 R )-4-(trifluoromethyl)-2,3-dihydro-1 H -inden-1-yl]oxy}phenyl)propanoic acid, which was confirmed to have an enhancing effect on glucose-dependent insulin secretion after intravenous glucose injection in SD rats. [ABSTRACT FROM AUTHOR]

Abstract: The G protein-coupled receptor 40 (GPR40) mediates enhancement of glucose-stimulated insulin secretion in pancreatic β cells. The GPR40 agonist has been attracting attention as a novel insulin secretagogue with glucose dependency for the treatment of type 2 diabetes. The optimization study of compound 1 led to a potent and bioavailable GPR40 agonist 24, which showed insulin secretion and glucose lowering effects in rat OGTT. Compound 24 is a potential lead compound for a novel insulin secretagogue with a low risk of hypoglycemia. [Copyright &y& Elsevier]