Design, Synthesis, and Structure–Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) Inhibitors
| Autor: | Ke Ding, Jinfeng Luo, Cai-Hong Yun, Jianzhang Yang, Yanhui Huang, Zhengchao Tu, Marthandam Asokan Shibu, Lulu Kong, Xiaoyun Lu, Chih Yang Huang, Farheen BadrealamKhan |
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| Rok vydání: | 2019 |
| Předmět: |
Leucine zipper
p38 mitogen-activated protein kinases Rats Inbred WKY 01 natural sciences Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Rats Inbred SHR Drug Discovery Animals Humans Structure–activity relationship Spontaneous hypertensive rat Protein Kinase Inhibitors 030304 developmental biology Leucine Zippers Sulfonamides 0303 health sciences Drug discovery Kinase Chemistry Triazoles MAP Kinase Kinase Kinases Rats 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Biochemistry Drug Design Molecular Medicine Sterile alpha motif Lead compound |
| Zdroj: | Journal of Medicinal Chemistry. 63:2114-2130 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.9b00664 |
| Popis: | ZAK is a new promising target for discovery of drugs with activity against antihypertrophic cardiomyopathy (HCM). A series of 1,2,3-triazole benzenesulfonamides were designed and synthesized as selective ZAK inhibitors. One of these compounds, 6p binds tightly to ZAK protein (Kd = 8.0 nM) and potently suppresses the kinase function of ZAK with single-digit nM (IC50 = 4.0 nM) and exhibits excellent selectivity in a KINOMEscan screening platform against a panel of 403 wild-type kinases. This compound dose dependently blocks p38/GATA-4 and JNK/c-Jun signaling and demonstrates promising in vivo anti-HCM efficacy upon oral administration in a spontaneous hypertensive rat (SHR) model. Compound 6p may serve as a lead compound for new anti-HCM drug discovery. |
| Databáze: | OpenAIRE |
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