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Design, synthesis and biological evaluation of 4-fluoropyrrolidine-2-carbonitrile and octahydrocyclopenta[b]pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors.
- Source :
-
European Journal of Medicinal Chemistry . Oct2014, Vol. 86, p242-256. 15p. - Publication Year :
- 2014
-
Abstract
- Based on the previous work in our group and the principle of computer-aided drug design, a series of novel β-amino pyrrole-2-carbonitrile derivatives was designed and synthesized. Compounds 8l and 9l were efficacious and selective DPP4 inhibitors resulting in decreased blood glucose in vivo . Compound 8l had moderate DPP4 inhibitory activity (IC 50 = 0.05 μM) and good oral bioavailability ( F = 53.2%). Compound 9l showed excellent DPP4 inhibitory activity (IC 50 = 0.01 μM), good selectivity (selective ratio: DPP8/DPP4 = 898.00; DPP9/DPP4 = 566.00) against related peptidases, and good efficacy in an oral glucose tolerance tests in ICR mice and moderate PK profiles ( F = 22.8%, t 1/2 = 2.74 h). Moreover, compound 9l did not block hERG channel and exhibited no inhibition of liver metabolic enzymes such as CYP2C9. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 86
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 98809619
- Full Text :
- https://doi.org/10.1016/j.ejmech.2014.08.059