title: Synthesis and biological evaluation of homopiperazine derivatives with beta-aminoacyl group as dipeptidyl peptidase IV inhibitors.
abstract: Compounds with homopiperazine skeleton are designed to find a potent DPP-IV inhibitor without inhibiting CYP. Thus a series of beta-aminoacyl-containing homopiperazine derivatives was synthesized and evaluated. Compounds with acid moiety were found to be potent inhibitors of DPP-IV without inhibiting CYP 3A4. More specifically, compound 7m showed nanomolar activity with no inhibition towards five subtypes of CYPs, was considered as a prototype for further derivatization. Based on its X-ray co-crystal structure with human DPP-IV, we identified compounds 7s and 7t which showed good in vitro activity, no CYP inhibition, and good selectivity.
authors.affiliation: Drug Discovery Division, Korea Research Institute of Chemical Technology, Yuseong-Gu, Daejeon 305-600, Republic of Korea. jhahn@krict.re.kr
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
authors.forename: Woul Seong
authors.initials: WS
authors.lastname: Park
authors.forename: Mi Ae
authors.initials: MA
authors.lastname: Jun
authors.forename: Mi Sik
authors.initials: MS
authors.lastname: Shin
authors.forename: Seung Kyu
authors.initials: SK
authors.lastname: Kang
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Kim
authors.forename: Sang Dal
authors.initials: SD
authors.lastname: Rhee
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
authors.forename: Kwang Rok
authors.initials: KR
authors.lastname: Kim
authors.forename: Sung Gyu
authors.initials: SG
authors.lastname: Kim
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Sang Kwon
authors.initials: SK
authors.lastname: Sohn
authors.forename: Nam Sook
authors.initials: NS
authors.lastname: Kang
authors.forename: Jie Oh
authors.initials: JO
authors.lastname: Lee
authors.forename: Duck Hyung
authors.initials: DH
authors.lastname: Lee
authors.forename: Hyae Gyeong
authors.initials: HG
authors.lastname: Cheon
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Kim
mesh_terms: D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry; D003920:Diabetes Mellitus / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D011719:Pyrazines / Q000494:pharmacology; D000068900:Sitagliptin Phosphate; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000494:pharmacology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D010879:Piperazines; D011719:Pyrazines; D014230:Triazoles; D000077489:Piperazine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000068900:Sitagliptin Phosphate