Discovery of a Flexible Triazolylbutanoic Acid as a Highly Potent Uric Acid Transporter 1 (URAT1) Inhibitor.
Molecules
; 21(11)2016 Nov 16.
Article
em En
| MEDLINE
| ID: mdl-27854343
ABSTRACT
In order to systematically explore and understand the structure-activity relationship (SAR) of a lesinurad-based hit (1c) derived from the replacement of the S atom in lesinurad with CH2, 18 compounds (1a-1r) were designed, synthesized and subjected to in vitro URAT1 inhibitory assay. The SAR exploration led to the discovery of a highly potent flexible URAT1 inhibitor, 1q, which was 31-fold more potent than parent lesinurad (IC50 = 0.23 µM against human URAT1 for 1q vs 7.18 µM for lesinurad). The present study discovered a flexible molecular scaffold, as represented by 1q, which might serve as a promising prototype scaffold for further development of potent URAT1 inhibitors, and also demonstrated that the S atom in lesinurad was not indispensable for its URAT1 inhibitory activity.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ácido Butírico
/
Transportadores de Ânions Orgânicos
/
Proteínas de Transporte de Cátions Orgânicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article