Journal of Medicinal Chemistry p. 7708 - 7721 (2019)
Update date:2022-08-05
Topics:
Jiang, Qikun
Zhang, Jiangnan
Tong, Peiyue
Gao, Yan
Lv, Yiqin
Wang, Changyuan
Luo, Meiling
Sun, Mengchi
Wang, Jian
Feng, Yao
Cao, Linlin
Wang, Gang
Wang, Yang
Kan, Qiming
Zhang, Tianhong
Wang, Yongjun
Liu, Kexin
Sun, Jin
He, Zhonggui
The cyclic dipeptides generally present lower affinity toward intestinal oligopeptide transporter 1 (PEPT1) than the linear dipeptides. JBP485 (cyclo(l-Hyp-l-Ser)) is a low-affinity substrate of PEPT1 with poor oral bioavailability. However, JBP923 (l-Hyp-l-Ser) is a high-affinity substrate of PEPT1 with high oral absorption. We hypothesize that the bioactivatable pseudo-tripeptidization prodrug strategy is promising to increase the affinity of cyclic dipeptides toward PEPT1. To test our hypothesis, we design five amino acid ester prodrugs of JBP485. Compared with JBP485, the optimal prodrug (JBP485-3-CH2-O-valine, J3V) demonstrates improved affinity of PEPT1, oral bioavailability in rats and beagle dogs. Moreover, J3V can dose-dependently protect against liver injury. Additionally, J3V is stable in the gastrointestinal tract, beneficial to the PEPT1-mediated membrane transport, and is bioactivated in the enterocytes and hepatic cells, essential to elicit its bioactivity. In summary, the bioactivatable pseudo-tripeptidization strategy shows potential in increasing affinity of PEPT1 to enhance oral bioavailability of cyclic dipeptides.
View MoreContact:+86-0760-85282375
Address:zhongjing road,zhongshan torch hi-tech industrial development zone
Global United Biotechnology Inc.
Contact:+86-21-61618568
Address:Room 309, Building 6, NO.135, Jinyu Road, Pudong
Ningbo Tide Imp. & Exp. Co., Ltd.
Contact:+86-571-8993 7933; +86-571-8993 6453
Address:7/F Anno Domini Building, Tower South, 8 Qiu Shi Road,Hangzhou,China.
Suzhou Credit International Trading Co., Ltd
Contact:+86-512-65398039
Address:Qingdeng, Hightech. District, Suzhou
Contact:86-21-50966856
Address:Building 5,300 Chuanzhan Road,Pudong New District,Shanghai
Doi:10.1002/hlca.19950780811
(1995)Doi:10.1021/jo01339a004
(1966)Doi:10.1002/jhet.1848
(2015)Doi:10.1021/ja01529a062
()Doi:10.1002/anie.201707362
(2017)Doi:10.1021/ic50061a005
(1968)