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A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current standard of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in vivo models of choroidal neovascularization (CNV) as the primary means of developing SAR related to efficacy from topical administration. Ultimately, this effort led to the discovery of acrizanib (LHA510), a small-molecule VEGFR-2 inhibitor with potency and efficacy in rodent CNV models, limited systemic exposure after topical ocular administration, multiple formulation options, and an acceptable rabbit ocular PK profile. [ABSTRACT FROM AUTHOR]

Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation. [ABSTRACT FROM AUTHOR]

Inductionof phase II antioxidant enzymes by activation of Nrf2/ARE pathwayhas been recognized as a promising strategy for the regulation ofoxidative stress-related diseases. Herein we report our effort onthe discovery and optimization of Nrf2 activators with 1,2,4-oxadiazolecore. Screening of an in-house collection containing 7500 compoundsby ARE-luciferase reporter assay revealed a moderate Nrf2 activator, 1. Aimed at obtaining more derivatives efficiently, molecularsimilarity search by the combination of 2D fingerprint-based and 3Dshape-based search was applied to virtually screening the Chemdivcollection. Three derivatives with the same core were identified tohave better inductivity of Nrf2 than 1. The best hit 4was selected as starting point for structurally optimization,leading to a much more potent derivative 32. It in vitroupregulated gene and protein level of Nrf2 as well as its downstreammarkers such as NQO1, GCLM, and HO-1. It remarkably suppressed inflammationin the in vivo LPS-challenged mouse model. Our results provide a newchemotype as Nrf2-ARE activators which deserve further optimizationwith the aim to obtain active anti-inflammatory agents through Nrf2-AREpathway. [ABSTRACT FROM AUTHOR]