title: Modeling assisted rational design of novel, potent, and selective pyrrolopyrimidine DPP-4 inhibitors.
abstract: 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.
authors.affiliation: Molecular Systems, Merck Research Laboratories, NJ, USA. yingduo_gao@merck.com
authors.forename: Ying-Duo
authors.initials: YD
authors.lastname: Gao
authors.forename: Dennis
authors.initials: D
authors.lastname: Feng
authors.forename: Robert P
authors.initials: RP
authors.lastname: Sheridan
authors.forename: Giovanna
authors.initials: G
authors.lastname: Scapin
authors.forename: Sangita B
authors.initials: SB
authors.lastname: Patel
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Wu
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Ranabir
authors.initials: R
authors.lastname: Sinha-Roy
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Thornberry
authors.forename: Ann E
authors.initials: AE
authors.lastname: Weber
authors.forename: Tesfaye
authors.initials: T
authors.lastname: Biftu
mesh_terms: 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
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011480:Protease Inhibitors; D011743:Pyrimidines