Structure-activity relationship investigation of Phe-Arg mimetic region of human glutaminyl cyclase inhibitors
- 주제(기타) Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic
- 설명문(일반) [Ngo, Van T. H.; Van-Hai Hoang; Nguyen Van Manh; Ann, Jihyae; Lee, Jeewoo] Seoul Natl Univ, Coll Pharm, Res Inst Pharmaceut Sci, Lab Med Chem, Seoul 08826, South Korea; [Phuong-Thao Tran] Hanoi Univ Pharm, Dept Med Chem, 13-15 Le Thanh Tong, Hanoi, Vietnam; [Kim, Eunhye; Cui, Minghua; Choi, Sun] Ewha Womans Univ, Coll Pharm, Natl Leading Res Lab Mol Modeling & Drug Design, Seoul 03760, South Korea; [Kim, Eunhye; Cui, Minghua; Choi, Sun] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Seoul 03760, South Korea; [Lee, Jiyoun] Sungshin Univ, Dept Global Med Sci, Seoul 01133, South Korea; [Kim, Hee; Ha, Hee-Jin; Choi, Kwanghyun; Kim, Young-Ho] Medifron DBT, Sandanro 349, Ansan 15426, Gyeonggi Do, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 PERGAMON-ELSEVIER SCIENCE LTD
- 발행년도 2018
- URI http://www.dcollection.net/handler/ewha/000000151610
- 본문언어 영어
- Published As http://dx.doi.org/10.1016/j.bmc.2018.04.040
초록/요약
Glutamyl cyclase (QC) is a promising therapeutic target because of its involvement in the pathogenesis of Alzheimer's disease. In this study, we developed novel QC inhibitors that contain 3-aminoalkyloxy-4-methoxyphenyl and 4-aminoalkyloxyphenyl groups to replace the previously developed pharmacophore. Several potent inhibitors were identified, showing IC50 values in a low nanomolar range, and were further studied for in vitro toxicity and in vivo activity. Among these, inhibitors 51 and 53 displayed the most potent A beta(N3pE) (40)-lowering effects in in vivo acute model with reasonable BBB penetration, without showing cytotoxicity and hERG inhibition. The molecular modeling analysis of 53 indicated that the salt bridge interaction and the hydrogen bonding in the active site provided a high potency. Given the potent activity and favorable BBB penetration with low cytotoxicity, we believe that compound 53 may serve as a potential candidate for anti-Alzheimer's agents. (C) 2018 Elsevier Ltd. All rights reserved.
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