| Title : Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin - Biftu_2007_Bioorg.Med.Chem.Lett_17_3384 |
| Author(s) : 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 |
| Ref : Bioorganic & Medicinal Chemistry Lett , 17 :3384 , 2007 |
|
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. |
| PubMedSearch : Biftu_2007_Bioorg.Med.Chem.Lett_17_3384 |
| PubMedID: 17433672 |
| Gene_locus related to this paper: human-DPP4 |
| Inhibitor | CHEMBL233360 Sitagliptin |
| Gene_locus | human-DPP4 |
| Structure | 2P8S |
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 (2007)
Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin
Bioorganic & Medicinal Chemistry Lett
17 :3384
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 (2007)
Bioorganic & Medicinal Chemistry Lett
17 :3384