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Karen Anderson, Sha-Mei Liao, Juergen Maibaum, Frederic Cumin, Omar Delgado, Andrea De Erkenez, Fang Liu, Upendra Argikar, Ron Newton, Bruce D Jaffee; A novel oral small molecule Factor D inhibitor blocks complement activation in the blood and ocular tissues. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4440.
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© ARVO (1962-2015); The Authors (2016-present)
Strong genetic associations in humans have implicated complement alternative pathway (AP) activation in age-related macular degeneration (AMD). Factor D (FD) inhibition is proposed as an attractive mechanism to reduce alternative pathway overactivity at the first and rate-limiting step of the AP.
First-in-class, reversible, non-covalent Factor D inhibitors were identified using structure-based drug design, employing a tailored chemical library and in silico docking. Potency was assessed initially in a biochemical enzymatic assay, followed by serum- and whole blood-based in vitro functional assays using zymosan to activate the AP and measuring deposition of membrane attack complex (MAC). Compound 6 was investigated in vivo using a humanized FD knock-in mouse pharmacodynamic (PD) model. In this model, intraperitoneal lipopolysaccharide (LPS) was used to activate complement, and AP breakdown products were monitored in the blood and the eye tissue. We also evaluated the inhibitor’s ability to block ex vivo serum complement activation after oral administration of the compound to cynomolgus monkeys.
The FD inhibitor 6 was very potent in 50% human whole blood with a half-maximal inhibitory value (IC50) of 71 nM. The compound dose-dependently inhibited LPS-induced generation of Ba and iC3b/C3d in blood and eye after oral gavage in mice, with complete suppression of the AP in both compartments at 100 mg/kg PO. Dose dependent inhibition of ex vivo complement activation in serum was also demonstrated after oral administration to monkeys, with an IC50 value of 3.6 µM.
Compound 6 represents a first-in-class reversible, selective, and potent small molecule FD inhibitor that is orally efficacious in a humanized mouse model and in a monkey ex vivo PD assay. Systemic dysregulation of the AP underlies a number of human diseases with apparent local manifestations, like age-related macular degeneration. Fully effective treatment of these diseases will likely require inhibition at the systemic level. Our findings support continued efforts aimed at developing oral AP-targeting therapies for complement-mediated diseases.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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