Chemistry:Fezagepras
Fezagepras (developmental code name PBI-4050), also known previously as setogepram, is an experimental drug which acts as a mixed agonist-antagonist for certain free fatty acid receptors, being an agonist at FFAR1 (GPR40) but an antagonist at GPR84.[1] It has antiinflammatory and anti-fibrotic effects and has reached Phase II human clinical trials for treatment of idiopathic pulmonary fibrosis.[2][3][4][5][6] However, development was discontinued for all indications in 2022.[1]
Medium-chain fatty acids are known to act as GPR84 agonists and have been found to produce inflammation and mediate aging-associated cognitive decline via this action.[7][8][9] Fezagepras has been found to block 3-hydroxyoctanoic acid (3-HOA)-mediated neuronal inhibition in the hippocampus and associated cognitive impairment in rodents.[7][8] Similarly, it blocked the detrimental effects of the medium-chain fatty acid-producing gut bacteria Parabacteroides goldsteinii on memory in rodents.[7][8] In addition, fezagepras restored youthful memory function in aged rodents.[7][8]
References
- ↑ 1.0 1.1 "Liminal BioSciences". 4 August 2022. https://adisinsight.springer.com/drugs/800030515.
- ↑ "Fatty acid receptor modulator PBI-4050 inhibits kidney fibrosis and improves glycemic control". JCI Insight 3 (10). May 2018. doi:10.1172/jci.insight.120365. PMID 29769449.
- ↑ "Phase 2 clinical trial of PBI-4050 in patients with idiopathic pulmonary fibrosis". The European Respiratory Journal 53 (3). March 2019. doi:10.1183/13993003.00663-2018. PMID 30578394.
- ↑ "PBI-4050 reduces pulmonary hypertension, lung fibrosis, and right ventricular dysfunction in heart failure". Cardiovascular Research 116 (1): 171–182. January 2020. doi:10.1093/cvr/cvz034. PMID 30753422.
- ↑ "Modulation of the G-Protein-Coupled Receptor 84 (GPR84) by Agonists and Antagonists". Journal of Medicinal Chemistry 63 (24): 15399–15409. December 2020. doi:10.1021/acs.jmedchem.0c01378. PMID 33267584.
- ↑ "A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40 and GPR84". The American Journal of Pathology 188 (5): 1132–1148. May 2018. doi:10.1016/j.ajpath.2018.01.009. PMID 29454750.
- ↑ 7.0 7.1 7.2 7.3 "Intestinal interoceptive dysfunction drives age-associated cognitive decline". Nature 652 (8109): 442–450. April 2026. doi:10.1038/s41586-026-10191-6. PMID 41813891.
- ↑ 8.0 8.1 8.2 8.3 "Rogue gut microbes derail memory". Immunity 59 (5): 1177–1179. May 2026. doi:10.1016/j.immuni.2026.04.008. PMID 42119367.
- ↑ "Stanford Scientists Reverse Age-Related Memory Loss by Targeting the Gut". 5 July 2026. https://scitechdaily.com/stanford-scientists-reverse-age-related-memory-loss-by-targeting-the-gut/.
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