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Design, synthesis and biological evaluation of a series of novel GPR40 agonists containing nitrogen heterocyclic rings.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2018 Oct 01; Vol. 28 (18), pp. 3050-3056. Date of Electronic Publication: 2018 Aug 02. - Publication Year :
- 2018
-
Abstract
- A novel series of GPR40 agonists is designed by introducing nitrogen-containing heterocyclic ring at the terminal phenyl ring of TAK-875 with the aim of decreasing its lipophilicity. Three different β-substituted phenylpropionic acids were investigated as the acidic components. A total of 34 compounds have been synthesized, among which, compound 30 exhibited comparable GPR40 agonistic activity in vitro with TAK-875 and relatively lower lipophilicity through calculation (30, EC <subscript>50</subscript> = 1.2 μM, cLogP = 1.3; TAK-875: EC <subscript>50</subscript> = 5.1 μM, cLogP = 3.4). Moreover, compound 30 was able to enhance the insulin secretion of primary islets isolated from normal ICR mice and showed no obvious inhibition against cytochromes P450 in vitro. In vivo, compound 30 exhibited efficacy in oral glucose tolerance test (oGTT) in normal ICR mice.<br /> (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Dose-Response Relationship, Drug
Isoindoles chemistry
Mice
Mice, Inbred ICR
Molecular Structure
Structure-Activity Relationship
Tetrahydroisoquinolines chemical synthesis
Tetrahydroisoquinolines chemistry
Drug Design
Isoindoles pharmacology
Receptors, G-Protein-Coupled agonists
Tetrahydroisoquinolines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 28
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 30097366
- Full Text :
- https://doi.org/10.1016/j.bmcl.2018.07.048