TABLE 5.

Synthetic molecules in preclinical studies.

Role	Medicine	Administraion	Mechanism	References
Anti-angiogenesis	YK-4–279	Intravitreal injection	Reduces neovascular tufts	Schafer et al. (2020)
	BT2	Intravitreal injection	Inhibitor of angiogenesis and vascular permeability by suppressing pERK-FosB/△FosB–VCAM-1 axis	Li et al. (2020b)
	UBX1967	Intravitreal injection	Targets elimination of senescent cells by inhibition of BCL-xL	Crespo-Garcia et al. (2021)
	NYY01	Intravitreal injection	Suppresses pathologic retinal neovascularization, microglial activation, and inflammatory cytokines; promotes reparative angiogenesis	Zhou et al. (2021)
	Boc-FLFLF	Subcutaneous injection	Inhibits neovessel formation	Rezzola et al. (2017)
	Linagliptin	Subcutaneous injection	Mediates GLP-1R-independent anti-angiogenic effects by inhibiting VEGFR downstream signaling	Kolibabka et al. (2018)
Prevent vascular leakage	CD5-2	Intravenous injection	Prevents vascular leakage by increasing expression of VE-cadherin, SMAD2/3 activity, and PDGF-B and reduces the activation of microglial cells	Ting et al. (2019)
	Ac-RLYE	Intravitreal injection	Prevents BRB breakdown and vascular leakage by antagonizing VEGFR-2	Park et al. (2021)
	BIRKI	Intravitreal injection	Restores RPE cell morphology and distribution, favors retinal capillary dilation, and reduces hypoxia and iBRB leakage	Lebon et al. (2021)
	β-agonists	Intraperitoneal injection	Activates PI3K/Akt signaling pathways in pericytes and attenuates pericyte loss and vascular leakage	Yun et al. (2018)
	Primaquine diphosphate	Oral	Prevents vascular leakage by maintaining endothelial integrity via ubiquitin specific protease 1 inhibition	Noh et al. (2021)
Anti-inflammatory	Semaglutide	Eye drops	Reduces glial activation, NF-κB, proinflammatory cytokines, and adhesion molecule-1; prevents RGC cell apoptosis; attenuates vascular leakage	Simo et al. (2021)
	BNN27	Intraperitoneal injection	Activates TrkA receptor and inhibits the diabetes-induced increase in p75NTR expression; decreases the activation of caspase-3, TNFa, and IL-1b; increases IL-10 and IL-4	Iban-Arias et al. (2018)
	Nimbolide	Intraperitoneal injection	Inhibits inflammation through the inhibition of the TLR4/NF-jB signaling pathway	Shu et al. (2021)
	Melatonin	Intraperitoneal injection	Inhibits inflammation and OS by enhancing the expression and activity of Sirt1	Tu et al. (2021b)
	SZV 1287	Subcutaneous injection	Inhibits AOC3; dual TRPA1/TRPV1 antagonistic activities; reduces the GFAP immunoreactivity of Müller cell processes	Tekus et al. (2021)
	Verapamil	Oral	Inhibits TLR4, TXNIP, and NLRP3-inflammasomes	Eissa et al. (2021)
	Tonabersat	Oral	Regulates assembly of NLRP3 via Connexin43 hemichannel block to reduce inflammation	Mat Nor et al. (2020)
	AMG487	Subcutaneous injection	Alleviates PDGFR-β and occludin loss and decreases the residual content of retinal albumin via the inhibition of OS and ER stress and activation of p38	Wang et al. (2019)
Neuroprotection	PF-05231023	Intraperitoneal injection	Reduces inflammatory marker IL1b mRNA levels; activates the Akt-Nrf2 pathway in photoreceptors	Fu et al. (2018b)
	rhNGF	Intravitreal injection/eye drop	Recovers optic nerve crush-induced RGC degeneration by reversing the proNGF/p75NTR increase and TrkA receptors activation	Mesentier-Louro et al. (2019)
	Liraglutide	Intravitreal injection	Arrests hyperphosphorylated tau-triggered retinal neurodegeneration via activation of GLP-1R/Akt/GSK3β signaling	Shu et al. (2019)
	Rapamycin	Intraperitoneal injection	Prolongs autophagy activation and improves RGC survival	Russo et al. (2018)
	hydroxytyrosol	Oral	Decreases peroxynitrite production; antiplatelet effect; protects endothelial prostacyclin production	Gonzalez-Correa et al. (2018)

BCL-xL, B cell lymphoma-xL; Boc-FLFLF, Boc-Phe-Leu-Phe-Leu-Phe; GLP-1R, glucagon-like peptide 1 receptor; VEGFR, vascular endothelial growth factor receptor; PDGF, platelet-derived growth factor; Ac-RLYE, N-acetylated Arg-Leu-Tyr-Glu; PI3K, phosphoinositide 3-kinase; TLR4, toll-like-receptor-4; TXNIP, thioredoxin-interacting protein; NLRP3, nucleotide-binding domain-like receptor protein-3; p75NTR, neurotrophin receptor p75; TrkA, tropomyosin-related kinase A; IL, interleukin; TRPA1/TRPV1, transient receptor potential ankyrin 1 and vanilloid 1; GFAP, glial fibrillary acidic protein; Keap1, Kelch-like erythroid-cell-derived protein with CNC homology-associated protein 1; BIRKI, Boehringer Ingelheim Rho kinase inhibitor; UPARANT, Ac-L-Arg-Aib-L-Arg-L-Cα(Me)Phe-NH2 tetrapeptide; Sirt1, silent information regulator factor 2-related enzyme 1; rhNGF, recombinant human nerve growth factor; GSK3β, glucogen synthase kinase 3