Synthesis and biological evaluation of homopiperazine derivatives with beta-aminoacyl group as dipeptidyl peptidase IV inhibitors.

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Ahn JH, Park WS, Jun MA, Shin MS, Kang SK, Kim KY, Rhee SD, Bae MA, Kim KR, Kim SG, Kim SY, Sohn SK, Kang NS, Lee JO, Lee DH, Cheon HG, Kim SS

Synthesis and biological evaluation of homopiperazine derivatives with beta-aminoacyl group as dipeptidyl peptidase IV inhibitors.

Bioorg Med Chem Lett. 2008 Dec 15;18(24):6525-9. doi: 10.1016/j.bmcl.2008.10.076. Epub 2008 Oct 21.

PubMed ID

18996694 [ View in PubMed

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Abstract

Compounds with homopiperazine skeleton are designed to find a potent DPP-IV inhibitor without inhibiting CYP. Thus a series of beta-aminoacyl-containing homopiperazine derivatives was synthesized and evaluated. Compounds with acid moiety were found to be potent inhibitors of DPP-IV without inhibiting CYP 3A4. More specifically, compound 7m showed nanomolar activity with no inhibition towards five subtypes of CYPs, was considered as a prototype for further derivatization. Based on its X-ray co-crystal structure with human DPP-IV, we identified compounds 7s and 7t which showed good in vitro activity, no CYP inhibition, and good selectivity.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(2R)-4-(2-BENZOYL-1,2-DIAZEPAN-1-YL)-4-OXO-1-(2,4,5-TRIFLUOROPHENYL)BUTAN-2-AMINE	Dipeptidyl peptidase 4	IC 50 (nM)	70	N/A	N/A	Details