Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin.
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.
Biftu
Tesfaye
T
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. Tesfaye_Biftu@merck.com
Scapin
Giovanna
G
Singh
Suresh
S
Feng
Dennis
D
Becker
Joe W
JW
Eiermann
George
G
He
Huaibing
H
Lyons
Kathy
K
Patel
Sangita
S
Petrov
Aleksandr
A
Sinha-Roy
Ranabir
R
Zhang
Bei
B
Wu
Joseph
J
Zhang
Xiaoping
X
Doss
George A
GA
Thornberry
Nancy A
NA
Weber
Ann E
AE
D058892:Adenosine Deaminase Inhibitors; D000284:Administration, Oral; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003514:Cyclohexylamines / Q000737:chemistry*; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D015195:Drug Design; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
D058892:Adenosine Deaminase Inhibitors; D003514:Cyclohexylamines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006023:Glycoproteins; D017320:HIV Protease Inhibitors; D011719:Pyrazines; D014230:Triazoles; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate