Syntheses of 1-substituted-3-aminopyrazoles

A series of 1-substituted-3-aminopyrazoles were prepared via Chan-Lam coupling reactions, alkylation, and pyrazole ring formation

One-pot synthesis of 2-aminobenzimidazoles using 2-chloro-1,3-dimethylimidazolinium chloride (DMC)

2-Chloro-1,3-dimethylimidazolinium chloride (DMC or DMC-Cl) has been found to effectively and rapidly generate 2-aminobenzimidazoles from 1,2-diaminoarenes and isothiocyanates in moderate to good yields at room temperature in a one-pot operation

Unified approach to prenylated indole alkaloids: total syntheses of (−)-17-hydroxy-citrinalin B, (+)-stephacidin A, and (+)-notoamide I

A unified strategy for the synthesis of congeners of the prenylated indole alkaloids is presented. This strategy has yielded the first synthesis of the natural product (–)-17-hydroxy-citrinalin B as well as syntheses of (+)-stephacidin A and (+)-notoamide I. An enolate addition to an in situ generated isocyanate was utilized in forging a key bicyclo[2.2.2]diazaoctane moiety, and in this way connected the two structural classes of the prenylated indole alkaloids through synthesis

Discovery of Oral VEGFR-2 Inhibitors That Provide Sustained Ocular Retention and Efficacy in Models of Wet-AMD

The benefit of intravitreal anti-VEGF therapy in treating wet age-related macular degeneration (AMD) has been well established. Identification of suitable VEGFR-2 inhibitors would provide alternative dosing opportunities beyond intravitreal injection. To identify such inhibitors, we employed a high–throughput in vivo screening strategy with a model of choroidal neovascularization and iterative compound design to provide VEGFR-2 inhibitors with potential to benefit wet AMD patients. These compounds, when dosed orally, provided good efficacy and preferential ocular tissue distribution while minimizing systemic exposure

The discovery of N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (acrizanib), a VEGFR-2 inhibitor specifically designed for topical ocular delivery, as a therapy for neovascular age- related macular degeneration

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 smallmolecule 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