Subjects: Physics >> General Physics: Statistical and Quantum Mechanics, Quantum Information, etc. submitted time 2017-11-17
Shaogao Zeng
Hui Xiea
Lili Zeng
Xin Lu
Xin Zhao
Guicheng Zhang
Zhengchao Tu
Hongjiang Xu
Ling Yang
Xiquan Zhang
Wenhui Hu
Abstract： A new chemical class of potent DPP-IV inhibitors has been structurally derived from our recently disclosed pyrrolopyrimidine scaffold by replacing cyanobenzyl with butynyl group. Systematic variations and structure-activity relationship studies have been conducted on the starting hit 51 (IC50= 0.46 μM). Consequently, compound 78 (IC50= 1.55 nM) was identified to be a potent, selective, and orally available lead, worth further evaluations and optimizations.
Peer Review Status:
Awaiting Review
Subjects: Biology >> Ecology submitted time 2017-11-17
Hui Xie
Saogao Zeng
Lili Zeng
Xiaobing Lan
Guicheng Zhang
Li Liu
Xin Lu
Na Chen
Zhiyuan Li
Zengzhao Tu
Hongjiang Xu
Ling Yang
Xiquan Zhang
Wenhui Hu
Abstract： Followed pharmacological evaluation exposed an extensive hepatic first pass effect within our recently disclosed DPP-IV inhibitors bearing thienopyrimidine scaffold. Through scaffold replacement with pyrrolopyrimidine, compound 1a had substantially improved the metabolic stability (from 6.6% to 65.07%), yet with severely poor absorptive property. Further modification by incorporation with varied substituents and structure conversion yielded both permeable and metabolic stable compounds. The whole pharmacokinetic- property based optimization had succeeded in balancing overall properties and resulted in the compound 1j, that with excellent efficacy to be a potential anti-diabetic candidate.
Peer Review Status:Awaiting Review
Subjects: Biology >> Ecology submitted time 2017-11-17
Abstract： It is urgent to discover new anti-influenza drugs considering the threat of so called swine flu and Spanish flu. Though Adamantane derivatives are the only M2 inhibitors as anti-influenza virus A drugs, they are limited to use in the US due to drug resistant. Herein we reported that multiple lead compounds as M2 inhibitors were rapidly generated through the screening of focused library designed with scaffold-hopping strategy based on Amantadine.
Peer Review Status:Awaiting Review
Subjects: Biology >> Ecology submitted time 2017-11-17
Abstract： The discovery of new anti-influenza drugs is urgent, particularly considering the recent threat of swine flu. Although amantadine derivatives are the only M2 drugs for influenza virus A, their use is limited in the US due to drug resistance. Here we report the discovery of multiple M2 inhibitor lead compounds that were rapidly generated through focused screening of a small primary amine library which was designed using a scaffold-hopping strategy based on amantadine.
Peer Review Status:Awaiting Review
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