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Bioorg Med Chem. 2013 Apr 1;21(7):1749-55. doi: 10.1016/j.bmc.2013.01.062. Epub 2013 Feb 8.

Discovery of potent dipeptidyl peptidase IV inhibitors through pharmacophore hybridization and hit-to-lead optimization.

Author information

1
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou 510530, China.

Abstract

A novel dipeptidyl peptidase IV inhibitor hit (5, IC50=0.86 μM) was structurally derived from our recently disclosed preclinical candidate 4 by replacing the cyanobenzyl with a butynyl based on pharmacophore hybridization. A hit-to-lead optimization effort was then initiated to improve its potency. Most N-substituted analogs exhibited good in vitro activity, and compound 18o (IC50=1.55 nM) was identified to be a potent dipeptidyl peptidase IV inhibitor with a significantly improved pharmacokinetic properties (bioavailablity: 41% vs 82.9%; T1/2: 2h vs 4.9h).

PMID:
23434133
DOI:
10.1016/j.bmc.2013.01.062
[Indexed for MEDLINE]

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