title: Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization.
abstract: We previously reported a highly potent DPP-IV inhibitor 6 with low in vivo efficacy. While trying to maintain consistent in vitro and in vivo biological activity, we initiated a pharmacokinetic property-driven optimization to improve the metabolic stability and permeability of inhibitor 6. A simple scaffold replacement of thienopyrimidine with pyrrolopyrimidine (21a) led to significantly improved metabolic stability (4% vs. 65% remaining). Further modification of the pyrrolopyrimidine scaffold to produce compound 21j resulted in much better oral bioavailability than 6. Importantly, compound 21j exhibits greater in vivo efficacy than does 6 and Alogliptin and is worthy of further development.
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kai Yuan Avenue, Guangzhou Science Park, Guangzhou 510530, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xie
authors.forename: Lili
authors.initials: L
authors.lastname: Zeng
authors.forename: Shaogao
authors.initials: S
authors.lastname: Zeng
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.forename: Guicheng
authors.initials: G
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Na
authors.initials: N
authors.lastname: Cheng
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Tu
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Li
authors.forename: Hongjiang
authors.initials: H
authors.lastname: Xu
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Xiquan
authors.initials: X
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Junling
authors.initials: J
authors.lastname: Zhao
authors.forename: Wenhui
authors.initials: W
authors.lastname: Hu
mesh_terms: D000042:Absorption; D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015195:Drug Design; D004355:Drug Stability; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011743:Pyrimidines; D011758:Pyrroles; C527741:pyrrolopyrimidine; D018819:Dipeptidyl Peptidase 4