Discovery of Potent and Selective Dipeptidyl Peptidase IV Inhibitors Derived from β-Aminoamides Bearing Subsituted Triazolopiperazines

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• 作者：Dooseop Kim ; Jennifer E. Kowalchick ; Linda L. Brockunier ; Emma R. Parmee ; George J. Eiermann ; Michael H. Fisher ; Huaibing He ; Barbara Leiting ; Kathryn Lyons ; Giovanna Scapin ; Sangita B. Patel ; Aleksan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：February 14, 2008
• 年：2008
• 卷：51
• 期：3
• 页码：589 - 602
• 全文大小：690K
• 年卷期：v.51,no.3(February 14, 2008)
• ISSN：1520-4804

文摘

A series of β-aminoamides bearing triazolopiperazines have been discovered as potent, selective, and orally active dipeptidyl peptidase IV (DPP-4) inhibitors by extensive structure–activity relationship (SAR) studies around the triazolopiperazine moiety. Among these, compound 34b with excellent in vitro potency (IC₅₀ = 4.3 nM) against DPP-4, high selectivity over other enzymes, and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in lean mice. On the basis of these properties, compound 34b has been profiled in detail. Further refinement of the triazolopiperazines resulted in the discovery of a series of extremely potent compounds with subnanomolar activity against DPP-4 (42b−49b), that is, 4-fluorobenzyl-substituted compound 46b, which is notable for its superior potency (IC₅₀ = 0.18 nM). X-ray crystal structure determination of compounds 34b and 46b in complex with DPP-4 enzyme revealed that (R)-stereochemistry at the 8-position of triazolopiperazines is strongly preferred over (S) with respect to DPP-4 inhibition.