The isomerohydrolase RPE65, which catalyzes conversion of all-trans-retinyl palmitate to 11-cis-retinol and is the rate-limiting step in the visual cycle, offers a potential therapeutic intervention point for modulating the visual cycle. (R)-Emixustat, a potent RPE65 inhibitor, did not meet endpoints in clinical trials for dry AMD and STGD1 due to a narrow therapeutic index and poor pharmacokinetics (PK). The poor PK of (R)-emixustat is largely attributed to vascular adhesion protein-1 (VAP-1)-mediated oxidative metabolism.
Together with Dr. Konstantin Petrukhin at Columbia University (https://www.vagelos.columbia.edu/profile/konstantin-petrukhin-phd) and Dr. Gennadiy Moiseyev at Wake Forest University (https://school.wakehealth.edu/faculty/m/gennadiy-moiseyev), we previously reported that novel RPE65 inhibitor (±)-RPE65-61 modulated the visual cycle in vivo and conferred neuroprotective effects in the murine LIRD model. We are currently engaged in drug discovery efforts that generate analogues of (±)-RPE65-61 as part of a structure-activity relationship (SAR) campaign designed to further improve RPE65 potency while blunting VAP-1-mediated oxidation. Our goal is to identify novel and orally bioavailable RPE65 inhibitors with suitable potency, efficacy, safety, and improved PK profile relative to (R)-emixustat.
Funding: NIH 1R01EY034461-01
Wang, Y.; Ma, X., Muthuraman, P.; Raja, R.; Jayaraman, A.; Petrukhin, K.; Cioffi, C. L.; Ma, J-X.; Moiseyev, G. The novel visual cycle inhibitor (±)-RPE65-61 protects retinal photoreceptors from light-induced degeneration. PloS ONE 2022, 17(10), e0269437.
Konstantin Petrukhin, Christopher L. Cioffi, Yuhong Wang, Jian-xing Ma, Gennadiy Moiseyev; Novel Isomerohydrolase Inhibitor for Treatment of Atrophic Form of Age-related Macular Degeneration and Stargardt Disease; U.S. Provisional Application No. 63/212,384, filed June 18, 2021 – CTV Ref. IR CU21263; Our Docket 91717-PRO.
Shin, Y,; Moiseyev, G.; Petrukhin, K.; Cioffi, C. L.; Muthuraman, P.; Takahashi, Y.; Ma, J. X. A novel RPE65 inhibitor CU239 suppresses visual cycle and prevents retinal degeneration. Biochim. Biophys. Acta. 2018,1864, 2420-2429; PMID: 29684583.
