Understanding metabolism related differences in ocular efficacy of MGV354.

was being developed as a novel ocular therapy for lowering of intraocular pressure, a key modifiable risk factor for glaucoma. is an activator of soluble guanylate cyclase, an enzyme known to be involved in the regulation of IOP. has been shown to robustly lower IOP over 24 hours after a single topical ocular drop in rabbit and monkey pharmacology models. However, failed to produce similar results in patients with ocular hypertension or open-angle glaucoma.With an objective of explaining the lack of efficacy in the clinic, we attempted to study whether human metabolism was significantly different from animal metabolism. The present study documents the investigation of metabolism of in an effort to understand potential differences in biotransformation pathways of in rabbits, monkeys, and humans.Overall twenty-six metabolites, formed via oxidative and conjugative pathways, were identified and . hepatic metabolism was qualitatively similar across species, with minor but distinct differences. There were no observable interspecies differences in the hepatic and ocular metabolism of . Although ocular metabolism was not as extensive as hepatic, the results do not explain the lack of efficacy of in clinical studies.