Nello Mainolfi

Copper-catalyzed decarboxylative C–N coupling for N-arylation

A novel approach for N-arylation utilizing aryl carboxylic acids as stable, inexpensive and widely available arylating reagents was developed. Employing a simple copper(II)–phenanthroline catalyst system, several benzoic acids bearing suitable ortho-substitutions undergo decarboxylative C–N cross-coupling effectively with various N-nucleophiles.

Continuous Flow Coupling and Decarboxylation Reactions Promoted by Copper Tubing

A convenient and efficient flow method for Ullmann condensations, Sonogashira couplings, and decarboxylation reactions using a commercially available copper tube flow reactor (CTFR) is described. The heated CTFR effects these transformations without added metals (e.g., Pd), ligands, or reagents, and in greater than 90% yield in most cases examined.

Discovery of Oral VEGFR-2 Inhibitors with Prolonged Ocular Retention That Are Efficacious in Models of Wet Age-Related Macular Degeneration

The benefit of intravitreal anti-VEGF therapy in treating wet age-related macular degeneration (AMD) is well established. Identification of VEGFR-2 inhibitors with optimal ADME properties for an ocular indication provides opportunities for dosing routes beyond intravitreal injection. We employed a high-throughput in vivo screening strategy with rodent models of choroidal neovascularization and iterative compound design to identify VEGFR-2 inhibitors with potential to benefit wet AMD patients. These compounds demonstrate preferential ocular tissue distribution and efficacy after oral administration while minimizing systemic exposure.

An Effective Prodrug Strategy to Selectively Enhance Ocular Exposure of a Cannabinoid Receptor (CB1/2) Agonist

Glaucoma is a leading cause of vision loss and blindness, with increased intraocular pressure (IOP) a prominent risk factor. IOP can be efficaciously reduced by administration of topical agents. However, the repertoire of approved IOP-lowering drug classes is limited, and effective new alternatives are needed. Agonism of the cannabinoid receptors CB1/2 significantly reduces IOP clinically and experimentally. However, development of CB1/2 agonists has been complicated by the need to avoid cardiovascular and psychotropic side effects. 1 is a potent CB1/2 agonist that is highly excluded from the brain. In a phase I study, compound 1 eyedrops were well tolerated and generated an IOP-lowering trend but were limited in dose and exposure due to poor solubility and ocular absorption. Here we present an innovative strategy to rapidly identify compound 1 prodrugs that are efficiently metabolized to the parent compound for improved solubility and ocular permeability while maintaining low systemic exposures.

Core Replacements in a Potent Series of VEGFR-2 Inhibitors and Their Impact on Potency, Solubility, and hERG.

Anti-VEGF therapy has been a clinically validated treatment of age-related macular degeneration (AMD). We have recently reported the discovery of indole based oral VEGFR-2 inhibitors that provide sustained ocular retention and efficacy in models of wet-AMD. We disclose herein the synthesis and the biological evaluation of a series of novel core replacements as an expansion of the reported indole based VEGFR-2 inhibitor series. Addition of heteroatoms to the existing core and/or rearranging the heteroatoms around the 6-5 bicyclic ring structure produced a series of compounds that generally retained good on-target potency and an improved solubility profile. The hERG affinity was proven not be dependent on the change in lipophilicity through alteration of the core structure. A serendipitous discovery led to the identification of a new indole-pyrimidine connectivity: from 5-hydroxy to 6-hydroxyindole with potentially vast implication on the in vitro/in vivo properties of this class of compounds.

Chapter Twenty-Two - Recent Progress in Small-Molecule Agents Against Age-Related Macular Degeneration

Abstract Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness in industrialized countries. Drusen and hyper- or hypopigmentation of the retinal pigment epithelium (RPE) are the characteristics of early AMD (also known as dry AMD). This asymptomatic abnormality of the RPE advances to two forms of AMD with a permanent loss of vision: geographic atrophy (GA) and/or choroidal neovascularization (CNV or also known as wet AMD). Although significant progress has been made in recent years for the treatment of wet AMD using intravitreal injections of anti-vascular endothelial growth factor (VEGF) biologics, there is still a need for less invasive treatment options. Furthermore, unlike for wet AMD, there is currently no treatment available for dry AMD or GA. This review will cover three emerging therapeutic target classes of low molecular weight agents for AMD: anti-angiogenesis agents, visual cycle inhibitors, and complement pathway inhibitors.