Evolution of a 4-Benzyloxy-benzylamino Chemotype to Provide Efficacious, Potent, and Isoform Selective PPARα Agonists as Leads for Retinal Disorders
| Autor: | Henry Shin, Elmar Nurmemmedov, Adam S. Duerfeldt, Philip C. Bourne, Dinesh Nath, Jian Xing Ma, Dou Xiaozheng |
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| Rok vydání: | 2020 |
| Předmět: |
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 |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.9b01189 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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