title: 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.
abstract: 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.
authors.affiliation: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, Republic of China.
authors.forename: Hsu
authors.initials: H
authors.lastname: Tsu
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
authors.forename: Shiow-Ju
authors.initials: SJ
authors.lastname: Lee
authors.forename: Chung-Nien
authors.initials: CN
authors.lastname: Chang
authors.forename: Kuo-His
authors.initials: KH
authors.lastname: Kao
authors.forename: Mohane Selvaraj
authors.initials: MS
authors.lastname: Coumar
authors.forename: Yen-Ting
authors.initials: YT
authors.lastname: Yeh
authors.forename: Chia-Hui
authors.initials: CH
authors.lastname: Chien
authors.forename: Hsin-Sheng
authors.initials: HS
authors.lastname: Wang
authors.forename: Ke-Ta
authors.initials: KT
authors.lastname: Lin
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Chang
authors.forename: Ssu-Hui
authors.initials: SH
authors.lastname: Wu
authors.forename: Yuan-Shou
authors.initials: YS
authors.lastname: Chen
authors.forename: I-Lin
authors.initials: IL
authors.lastname: Lu
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Wu
authors.forename: Ting-Yueh
authors.initials: TY
authors.lastname: Tsai
authors.forename: Wei-Cheng
authors.initials: WC
authors.lastname: Chen
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Weir-Torn
authors.initials: WT
authors.lastname: Jiaang
mesh_terms: 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
chemical_list: 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