Title of article :
Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin
Author/Authors :
Tesfaye Biftu، نويسنده , , Giovanna Scapin، نويسنده , , Suresh Singh، نويسنده , , Dennis Feng، نويسنده , , Joe W. Becker، نويسنده , , George Eiermann، نويسنده , , Huaibing He، نويسنده , , Kathy Lyons، نويسنده , , Sangita Patel، نويسنده , , Aleksandr Petrov، نويسنده , , Ranabir Sinha-Roy، نويسنده , , Bei Zhang، نويسنده , , Joseph Wu، نويسنده , , Xiaoping Zhang، نويسنده , , George A. Doss، نويسنده , , Nancy A. Thornberry، نويسنده , , Ann E. Weber، نويسنده ,
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 β-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 (IC50 = 21 nM) with excellent in vivo activity and pharmacokinetic profile.
Keywords :
DPP-4 , sitagliptin , Januvia , Cyclohexylamine
