Sephin1 is a guanabenz derivative that binds to and inhibits a regulatory subunit of the stress-induced protein phosphatase 1 (PPP1R15A), but not the constitutive PPP1R15B, and lacks beta2-adrenergic activity. Phosphorylation of eIF2α, α subunit of eukaryotic translation initiation factor 2, reduces protein synthesis and prevents the accumulation of misfolded protein in the endoplasmic reticulum (ER). PPP1R15A recruits the serine/threonine-protein phosphatase PP1 to dephosphorylate eIF2α, so inhibiting PPP1R15A activity prolongs the phosphorylation of eIF2α and aids in its prevention of the accumulation of misfolded protein. In vitro, Sephin1 protected cells from lethal protein misfolding and cytotoxic ER stress. In vivo Sephin1 prevented Charcot-Marie-Tooth 1B and ALS diseases in mice.

AGE-RELATED MACULAR DEGENERATION (AMD), PROLIFERATIVE DIABETIC RETINOPATHY (PDR) AND DIABETIC MACULAR EDEMA (DME) are collectively characterized by VEGF mediated retinal leakage, angiogenesis, and an underlying inflammatory process. TargeGen's TG100801 is designed to inhibit a select group of kinases involved in those three processes. Currently approved drug based therapy for macular degeneration requires repeated injection into the eye. TG100801 is the first topically applied, VEGFR)/Src kinase inhibitor to advance into the clinic for the treatment of Age-related macular degeneration, diabetic retinopathy. The formation of new blood vessels (angiogenesis), blood vessel leakage, and inflammation contribute to the progression of the eye disease, which is the leading cause of irreversible, severe loss of vision in people 55 years of age and older in the developed world. In cell based assays, following topical instillation, TG100572, the active drug produced by conversion of TG100801 as it penetrates the eye, was shown to induce apoptosis in proliferating endothelial cells responsible for neovasculariztion and to inhibit inflammatory-mediated processes as measured by endotoxin-induced nitric oxide release in vitro.

Ruboxistaurin is an orally bioavailable, selective, potent inhibitor of protein kinase C β developed for treating diabetic retinopathy. In vitro and in vivo non-clinical models have demonstrated that Ruboxistaurin decreases PKC β activity and ameliorates many of the effects of PKC β on pathologic processes in the retina. Ruboxistaurin prevents the slowing of retinal blood flow that is observed by fluorescein video angiography in the eyes of diabetic rats. It is also reported to cause regression of retinal neovascularization produced by laser-induced major branch vein occlusions in a porcine model. Ruboxistaurin positively affected the diabetes-induced retinal blood flow abnormalities in a Phase Ib study in diabetic patients. Ruboxistaurin is in phase III clinical trials for the treatment of diabetic nephropathy and diabetic macular edema. Eli Lilly had submitted Ruboxistaurin for approval in the US and the EU; however, the company subsequently discontinued development as it was unable to demonstrate sufficient efficacy

Pfizer's CP-547632 is a selective inhibitor of VEGFR-2 tyrosine kinase that was discovered during Pfizer's collaboration with OSI Pharmaceuticals. CP-547632, was identified as a potent inhibitor of the VEGFR-2 and basic fibroblast growth factor (FGF) kinases (IC(50) = 11 and 9 nM, respectively). It is selective relative to epidermal growth factor receptor, platelet-derived growth factor beta, and other related TKs. It also inhibits VEGF-stimulated autophosphorylation of VEGFR-2 in a whole cell assay with an IC(50) value of 6 nM. After oral administration of CP-547632 to mice bearing NIH3T3/H-ras tumors, VEGFR-2 phosphorylation in tumors was inhibited in a dose-dependent fashion (EC(50) = 590 ng/ml). CP-547,632 is a well-tolerated, orally-bioavailable inhibitor presently under clinical investigation for the treatment of human malignancies. CP-547632 is in phase I for the treatment of diabetic retinopathy and age-related macular degeneration.

Bimoclomol is the non-toxic heat shock protein (HSP) coinducer, which was shown to display multilateral protective activities against various forms of stress or injuries at the level of the cell, tissue or organism. Bimoclomol binds to HSF-1 and induces a prolonged binding of HSF-1 to the respective DNA elements. Bimoclomol reached the end of the Phase II clinical trial in a group of 410 patients with diabetic complications. Preclinical it was tested as a promising therapeutic agent against Diabetic neuropathies; Ischaemic heart disorders and other diseases.

Tenilsetam (CAS 997: ( /-)-3-(2-thienyl)-2-piperazinone), a cognition-enhancing drug successfully used for the treatment of patients suffering from Alzheimer's disease. According to the mechanism proposed, it inhibits advanced glycation end-product (AGE) formation. The beneficial effect of tenilsetam in Alzheimer's disease could come from the interference with AGE-derived crosslinking of amyloid plaques and a decreased inflammatory response to diminished activation of phagocytosing microglia. In addition was shown, that the long-term treatment with tenilsetam inhibited the formation of acellular capillaries without correcting pericyte loss. Was suggested that tenilsetam could be useful for the treatment of early diabetic retinopathy, but then these studies were discontinued.

IMD-0354 is an inhibitor of IκB kinase-β (IKKβ) that blocks NF-κB nuclear translocation. Attenuates myocardial ischemia/reperfusion injury by decreasing expression of adhesion molecules ICAM-1 and P-selectin and inhibiting cytokine and chemokine production in cardiomyocytes. Induces G0/G1 cell cycle arrest and apoptosis in HMC-1 and breast cancer cells. IMD-0354 had been in phase I clinical trials for the treatment of atopic dermatitis.

Beta-Amyrin Acetate is β-Amyrin derivative with potent anti-inflammatory, anti-diabetic, anti-hyperlipidemic activities.

Moxisylyte, also known as thymoxamine, is a drug used in urology for the treatment of erectile dysfunction, also was studied, that this drug may be useful to treat ocular disorders such as diabetic retinopathy. It is an alpha1-adrenergic antagonist. Was developed for self-injection therapy in France and marketed in several European countries as Icavex. In the spring 2005 the manufacturer of Icavex decided to withdraw this drug from Europe market, presumable due to its low market shares.

Parmidin (pyridinol carbamate) is a Soviet drug, has anti-arteriosclerotic (increased vascular resistance) activity, reduces the permeability of blood vessels, it helps to restore disturbed microcirculation in pathological processes. This is mainly due to the influence on kinin system, especially with a decrease in the activity of bradykinin receptors. It also reduces the aggregation of platelets. It’s used to treat: the brain vascular atherosclerosis, heart, limbs; diabetic retinopathy (non-inflammatory lesion of the retina associated with increased levels of sugar in the blood); thrombosis (violation of patency) retinal vein; occlusive disease (inflammation of the inner lining of arteries with a decrease in their lumen); trophic leg ulcers (slow-healing skin defects caused by malnutrition). Ointment is used in neurodermatitis (skin disease caused by disturbance of the central nervous system), Lichen sclerosus (teardrop scleroderma) genital organs of children, as well as a prophylactic and therapeutic agent against radiation skin lesions.