2-[3-[2-[(2S)-2-Cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]- 1,2,3,4-tetrahydroisoquinoline: a potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV.
Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a new type of antidiabetic drugs. Most known DPP-IV inhibitors often resemble the dipeptide cleavage products, with a proline mimic at the P1 site. As off-target inhibitions of DPP8 and/or DPP9 have shown profound toxicities in the in vivo studies, it is important to develop selective DPP-IV inhibitors for clinical usage. To achieve this, a new class of 2-[3-[[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethyl]amino]-1-oxopropyl]-based DPP-IV inhibitors was synthesized. SAR studies resulted in a number of DPP-IV inhibitors, having IC(50) values of <50 nM with excellent selectivity over both DPP8 (IC(50) > 100 microM) and DPP-II (IC(50) > 30 microM). Compound 21a suppressed the blood glucose elevation after an oral glucose challenge in Wistar rats and also inhibited plasma DPP-IV activity for up to 4 h in BALB/c mice. The results show that compound 21a possesses in vitro and in vivo activities comparable to those of NVP-LAF237 (4), which is in clinical development.
Tsu
Hsu
H
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, Republic of China.
Chen
Xin
X
Chen
Chiung-Tong
CT
Lee
Shiow-Ju
SJ
Chang
Chung-Nien
CN
Kao
Kuo-His
KH
Coumar
Mohane Selvaraj
MS
Yeh
Yen-Ting
YT
Chien
Chia-Hui
CH
Wang
Hsin-Sheng
HS
Lin
Ke-Ta
KT
Chang
Ying-Ying
YY
Wu
Ssu-Hui
SH
Chen
Yuan-Shou
YS
Lu
I-Lin
IL
Wu
Su-Ying
SY
Tsai
Ting-Yueh
TY
Chen
Wei-Cheng
WC
Hsieh
Hsing-Pang
HP
Chao
Yu-Sheng
YS
Jiaang
Weir-Torn
WT
D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D004150:Dipeptidases / Q000037:antagonists & inhibitors; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000187:drug effects*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors; D004353:Drug Evaluation, Preclinical; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005947:Glucose / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013997:Time Factors
C507822:2-(3-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino)-3-methyl-1-oxobutyl)-1,2,3,4-tetrahydroisoquinoline; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D011760:Pyrrolidinones; D004150:Dipeptidases; C471241:DPP9 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100151:dipeptidyl peptidase II; C487997:DPP8 protein, human; D018819:Dipeptidyl Peptidase 4; D005947:Glucose