Evolution of a 4-Benzyloxy-benzylamino Chemotype to Provide Efficacious, Potent, and Isoform Selective PPARα Agonists as Leads for Retinal Disorders

  • J Med Chem. 2020 Mar 26;63(6):2854-2876. doi: 10.1021/acs.jmedchem.9b01189.
Xiaozheng Dou  1  2 ,  Dinesh Nath  1  2 ,  Henry Shin  3 ,  Elmar Nurmemmedov  4 ,  Philip C Bourne  2 ,  Jian-Xing Ma  3 ,  Adam S Duerfeldt  1  2
Affiliations
  • 1. Institute for Natural Products Applications and Research Technologies, University of Oklahoma, 101 Stephenson Parkway, Stephenson Life Sciences Research Center, Norman, Oklahoma 73019, United States.
  • 2. Department of Chemistry & Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Stephenson Life Sciences Research Center, Norman, Oklahoma 73019, United States.
  • 3. Department of Physiology, University of Oklahoma Health Sciences Center, 941 Stanton L. Young Boulevard, Oklahoma City, Oklahoma 73104, United States.
  • 4. John Wayne Cancer Institute & Pacific Neuroscience Institute at Providence Saint John's Health Center, 2200 Santa Monica Boulevard, Santa Monica, California 90404, United States.
PMID: 32096640 DOI: 10.1021/acs.jmedchem.9b01189
Abstract

Peroxisome Proliferator-activated Receptor alpha (PPARα) is expressed in retinal Müller cells, endothelial cells, and in retinal pigment epithelium; 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 streptozotocin-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 analogues, which led to the discovery of 4u and related compounds that reach cellular potencies <50 nM and exhibit >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.

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