Synthesis and biological evaluation of homopiperazine derivatives with beta-aminoacyl group as dipeptidyl peptidase IV inhibitors.
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.
Ahn
Jin Hee
JH
Drug Discovery Division, Korea Research Institute of Chemical Technology, Yuseong-Gu, Daejeon 305-600, Republic of Korea. jhahn@krict.re.kr
Park
Woul Seong
WS
Jun
Mi Ae
MA
Shin
Mi Sik
MS
Kang
Seung Kyu
SK
Kim
Ki Young
KY
Rhee
Sang Dal
SD
Bae
Myung Ae
MA
Kim
Kwang Rok
KR
Kim
Sung Gyu
SG
Kim
Sun Young
SY
Sohn
Sang Kwon
SK
Kang
Nam Sook
NS
Lee
Jie Oh
JO
Lee
Duck Hyung
DH
Cheon
Hyae Gyeong
HG
Kim
Sung Soo
SS
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
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