A non-retinoid antagonist of retinol-binding protein 4 rescues phenotype in a model of Stargardt disease without inhibiting the visual cycle

Abstract

A primary pathological defect in the heritable eye disorder Stargardt disease is excessive accumulation of cytotoxic lipofuscin bisretinoids in the retina. Age-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE) matches the age-dependent increase in the incidence of the atrophic (dry) form of age-related macular degeneration (AMD) and therefore may be one of several pathogenic factors contributing to AMD progression. Lipofuscin bisretinoid synthesis in the retina depends on the influx of serum retinol from the circulation into the RPE. Formation of the tertiary retinol-binding protein 4 (RBP4)-transthyretin-retinol complex in the serum is required for this influx. Herein, we report the pharmacological effects of the non-retinoid RBP4 antagonist, BPN-14136. BPN-14136 dosing in the mouse model of increased lipofuscinogenesis significantly reduced serum RBP4 levels and inhibited bisretinoid synthesis, and this inhibition correlated with a partial reduction in visual cycle retinoids such as retinaldehydes serving as bisretinoid precursors. BPN-14136 administration at doses inducing maximal serum RBP4 reduction did not produce changes in the rate of the visual cycle, consistent with minimal changes in dark adaptation. mice exhibited dysregulation of the complement system in the retina, and BPN-14136 administration normalized the retinal levels of proinflammatory complement cascade components such as complement factors D and H, C-reactive protein, and C3. We conclude that BPN-14136 has several beneficial characteristics, combining inhibition of bisretinoid synthesis and reduction in retinaldehydes with normalization of the retinal complement system. BPN-14136, or a similar compound, may be a promising drug candidate to manage Stargardt disease and dry AMD.

Comparative pharmacokinetics and pharmacodynamics of the advanced Retinol-Binding Protein 4 antagonist in dog and cynomolgus monkey

“…BPN-14136 exhibited overall good PK profile in both species (good oral bioavailability, moderate to low clearance and adequate exposure). The overall good PK profile of the compound in dog and NHP is consistent with good PK characteristics that BPN-14136 exhibited in our previous rat [27] and mouse [28] studies. Because the single oral dose administered in the dog PK study (2 mg kg −1 ) was lower than in PK experiments conducted in three other species (5 mg kg −1 in rat, mouse, and NHP) we compared exposure in four species by analyzing dose-normalized AUC inf and C max values (Fig 2).…”

“…), no PXR activation, and no significant off-target activity at the hERG channel or within a standard screening panel of fifty-five GPCRs, enzymes, ion channels, and transporters [27]. The compound showed a good pharmacokinetic (PK) profile in rat [27] and mouse [28] and normalized disease phenotype in the mouse model of Stargardt disease [28]. Encouraged by very good rodent PK characteristics and good preclinical efficacy in the Stargardt disease model, we conducted PK and PD studies of BPN-14136 in dogs and non-human primates and extended in vitro ADME characterization of this compound.…”

“…BPN-14136 was synthesized as described previously [27,28]. In vitro ADME tests were conducted at AMRI, Albany, NY.…”

“…2 / 15 compound showed good PK characteristics in rodents (mouse and rat) coupled with significant in vivo efficacy (plasma RBP4 lowering) in both rodent species [27,28] which correlated with a desired partial reduction of retinaldehydes serving as direct bisretinoid precursors [28]. BPN-14136 dosing in the Abca4 -/mouse model of Stargardt disease significantly inhibited bisretinoid synthesis and normalized dysregulation of the complement system in the retina [28].…”

“…Retinol binding to RBP4 is required for the formation of the RBP4-TTR complex, as apo-RBP4 has reduced affinity for TTR [21,25]. We previously reported the discovery and characterization of several classes of nonretinoid RBP4 antagonists disrupting retinol-induced RBP4-TTR interaction [26][27][28][29][30]. One of the advanced analogs, BPN-14136 ( Fig 1) has optimal drug-like characteristics and demonstrates very good in vitro RBP4 binding potency as well as a strong in vitro ability to antagonize retinol-dependent RBP4 interaction with TTR [27].…”