Modeling assisted rational design of novel, potent, and selective pyrrolopyrimidine DPP-4 inhibitors.
Molecular modeling was used to improve potency of the cyclohexylamine series. In addition, a 3-D QSAR method was used to gain insight for reducing off-target DPP-8/9 activities. Compounds 3, 4, and 5 were synthesized and found to be potent DPP-4 inhibitors, in particular 4 and 5 are designed to be highly selective against off-target DASH enzymes while maintaining potency on DPP-4.
Gao
Ying-Duo
YD
Molecular Systems, Merck Research Laboratories, NJ, USA. yingduo_gao@merck.com
Feng
Dennis
D
Sheridan
Robert P
RP
Scapin
Giovanna
G
Patel
Sangita B
SB
Wu
Joseph K
JK
Zhang
Xiaoping
X
Sinha-Roy
Ranabir
R
Thornberry
Nancy A
NA
Weber
Ann E
AE
Biftu
Tesfaye
T
D054873:Dipeptidyl-Peptidase IV Inhibitors; D015195:Drug Design; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
D054873:Dipeptidyl-Peptidase IV Inhibitors; D011480:Protease Inhibitors; D011743:Pyrimidines