A novel small molecule ameliorates ocular neovascularisation and synergises with anti-VEGF therapy

Abstract

Ocular neovascularisation underlies blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. These diseases cause irreversible vision loss, and provide a significant health and economic burden. Biologics targeting vascular endothelial growth factor (VEGF) are the major approach for treatment. However, up to 30% of patients are non-responsive to these drugs and they are associated with ocular and systemic side effects. Therefore, there is a need for small molecule ocular angiogenesis inhibitors to complement existing therapies. We examined the safety and therapeutic potential of SH-11037, a synthetic derivative of the antiangiogenic homoisoflavonoid cremastranone, in models of ocular neovascularisation. SH-11037 dose-dependently suppressed angiogenesis in the choroidal sprouting assay ex vivo and inhibited ocular developmental angiogenesis in zebrafish larvae. Additionally, intravitreal SH-11037 (1 μM) significantly reduced choroidal neovascularisation (CNV) lesion volume in the laser-induced CNV mouse model, comparable to an anti-VEGF antibody. Moreover, SH-11037 synergised with anti-VEGF treatments in vitro and in vivo. Up to 100 μM SH-11037 was not associated with signs of ocular toxicity and did not interfere with retinal function or pre-existing retinal vasculature. SH-11037 is thus a safe and effective treatment for murine ocular neovascularisation, worthy of further mechanistic and pharmacokinetic evaluation.

Dietary Compound Chrysin Inhibits Retinal Neovascularization with Abnormal Capillaries in db/db Mice

“…Many anti-angiogenic drugs have been suggested as potential therapeutic agents in ocular diseases, such as retinopathy of prematurity in children, proliferative diabetic retinopathy in adults, and age-related macular degeneration in the elderly [36,37]. Biologics targeting against HIF/VEGF pathway causing the overexpression of angiogenic genes are the major approach for treatment.…”

“…Thus, the interaction of Ang proteins and Tie-2 may be a potential target for therapies in retinal vascular complications [21]. Modulation of VEGF signaling and Ang-2 expression has been proposed as a tool to correct the cellular mechanisms involved in the pathophysiology of diabetic retinal and choroidal vascular diseases [36]. This study revealed that the up-regulation of both Ang-2 and Tie-2 was inhibited in high glucose-exposed endothelial cells treated with chrysin and retinas of diabetic mice orally administrated chrysin.…”

Calcitriol and Non-Calcemic Vitamin D Analogue, 22-Oxacalcitriol, Attenuate Developmental and Pathological Ocular Angiogenesis Ex Vivo and In Vivo

“…Briefly, eyes of anesthetised mice were dilated with 1% tropicamide solution (Alcon, Fort Worth, TX, USA) and lubricated with Gonak hypromellose ophthalmic solution (Akorn, Lake Forest, IL, USA). Horizontal and vertical OCT images were taken per lesion and L-CNV lesion volumes were obtained using the quantification method previously established [30,31]. To assess vascular leakage, fluorescein angiography was performed on day 14 post L-CNV by i.p.…”

Synthesis of Natural Homoisoflavonoids Having Either 5,7-Dihydroxy-6-methoxy or 7-Hydroxy-5,6-dimethoxy Groups

“…Nevertheless, there have not been synthetic efforts towards such homoisoflavonoids since the synthesis of 4 and 9 was reported in 1971 [12]. A chemical synthesis of 5,6,7-trisubstituted homoisoflavonoids has the potential to provide a general and expedient entry into a plethora of analogues potentially with interesting biological activities [13–15]. Herein we report the first synthesis of cremastranone's derivatives in three or four steps from the known 4-chromenone, involving a chemoselective 1,4-reduction and manipulation of protecting groups.…”