Evolution of a 4-Benzyloxy-benzylamino Chemotype to Provide Efficacious, Potent, and Isoform Selective PPARα Agonists as Leads for Retinal Disorders
| العنوان: | Evolution of a 4-Benzyloxy-benzylamino Chemotype to Provide Efficacious, Potent, and Isoform Selective PPARα Agonists as Leads for Retinal Disorders |
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| المؤلفون: | Henry Shin, Elmar Nurmemmedov, Adam S. Duerfeldt, Philip C. Bourne, Dinesh Nath, Jian Xing Ma, Dou Xiaozheng |
| المصدر: | J Med Chem |
| بيانات النشر: | American Chemical Society (ACS), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Gene isoform, Benzylamines, Retinal Disorder, Alpha (ethology), Pharmacology, 01 natural sciences, Article, Streptozocin, Cell Line, Capillary Permeability, 03 medical and health sciences, Retinal Diseases, Drug Discovery, medicine, Animals, Humans, PPAR alpha, Receptor, Gene, 030304 developmental biology, 0303 health sciences, Diabetic Retinopathy, Retinal pigment epithelium, Chemotype, Chemistry, Peroxisome, Rats, 0104 chemical sciences, Disease Models, Animal, 010404 medicinal & biomolecular chemistry, medicine.anatomical_structure, Drug Design, Molecular Medicine, sense organs |
| الوصف: | Peroxisome proliferator-activated receptor alpha (PPARα) is expressed in retinal Müller cells, endothelial cells, and in retinal pigment epithelium, and agonism of PPARα with genetic or pharmacological tools ameliorates inflammation, vascular leakage, neurodegeneration, and neovascularization associated with retinal diseases in animal models. As such, PPARα is a promising drug target for diabetic retinopathy and age-related macular degeneration. Herein, we report proof-of-concept in vivo efficacy in an STZ-induced vascular leakage model (rat) and preliminary pharmacokinetic assessment of a first-generation lead 4a (A91). Additionally, we present the design, synthesis, and evaluation of second-generation analogs, which led to the discovery of 4u and related compounds that reach cellular potencies 2,700-fold selectivity for PPARα over other PPAR isoforms. These studies identify a pipeline of candidates positioned for detailed PK/PD and pre-clinical evaluation. |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3760d268dc4438d35be9e0f093bfeb63 https://doi.org/10.1021/acs.jmedchem.9b01189 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....3760d268dc4438d35be9e0f093bfeb63 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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