Synthesis of Azapeptide Ligands of the CD36 Receptor Towards Potential Treatments of Age-Related Macular Degeneration

摘要

The leading cause of blindness in North American adults, age-related macular degeneration (AMD) involves accumulation of sub-retinal deposits, degeneration of photoreceptors and choroidal neovascularization [1]. Targeting the CD36 receptor, because of its roles in oxidized lipid uptake and neovascularization [2], we have synthesized azapeptide analogues of growth hormone releasing peptide-6 (GHRP-6, His-D-Trp~Ala-Trp-D-Phe-Lys-NH2), such as [azaY~4]-and [A~1, azaF~4]-GHRP-6 (1 and 2), which bind to this scavenger receptor without significant affinity for the growth hormone secretagogue receptor la (GHS-Rla, Table 1) [3,4]. Azapeptides 1 and 2, both reduced inflammation; however, they exhibited opposite effects on neovascularization in a microvascular sprouting assay using mouse choroidal explants: the former suppressed angiogenesis and the latter exhibited angiogenic activity [3]. Considering subtle differences between the structures of 1 and 2 caused significant effects on neovascularization, we have now prepared a targeted library of azapeptide analogs to examine the influence of the 4-position aromatic residue. Employing the sub-monomer approach for solid-phase azapeptide synthesis [5], six analogs 7 were synthesized in which the phenol hydroxyl group of [azaY~4]-GHRP-6 was replaced by hydrogen and different electron withdrawing (F, CF3, N02, I) and donating (OCH3) substituent groups.