Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin.

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Biftu T, Scapin G, Singh S, Feng D, Becker JW, Eiermann G, He H, Lyons K, Patel S, Petrov A, Sinha-Roy R, Zhang B, Wu J, Zhang X, Doss GA, Thornberry NA, Weber AE

Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin.

Bioorg Med Chem Lett. 2007 Jun 15;17(12):3384-7. Epub 2007 Apr 2.

PubMed ID

17433672 [ View in PubMed

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Abstract

Molecular modeling was used to design a rigid analog of sitagliptin 1. The X-ray crystal structure of sitagliptin bound to DPP-4 suggested that the central beta-amino butyl amide moiety could be replaced with a cyclohexylamine group. This was confirmed by structural analysis and the resulting analog 2a was synthesized and found to be a potent DPP-4 inhibitor (IC(50)=21 nM) with excellent in vivo activity and pharmacokinetic profile.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Sitagliptin	Dipeptidyl peptidase 4	IC 50 (nM)	18	N/A	N/A	Details