Alexander Glenn Godfrey

A remote-controlled adaptive medchem lab: an innovative approach to enable drug discovery in the 21st Century.

This article describes our experiences in creating a fully integrated, globally accessible, automated chemical synthesis laboratory. The goal of the project was to establish a fully integrated automated synthesis solution that was initially focused on minimizing the burden of repetitive, routine, rules-based operations that characterize more established chemistry workflows. The architecture was crafted to allow for the expansion of synthetic capabilities while also providing for a flexible interface that permits the synthesis objective to be introduced and manipulated as needed under the judicious direction of a remote user in real-time. This innovative central synthesis suite is herein described along with some case studies to illustrate the impact such a system is having in expanding drug discovery capabilities.

Synergistic methodologies for the synthesis of 3-aroyl-2-arylbenzo[b]thiophene-based selective estrogen receptor modulators. Two concise syntheses of raloxifene

Difunctionalized benzo[b]thiophene intermediates are prepared which allow fully independent elaboration of the 2-aryl position or the tether position of benzo[b]thiophene-based selective estrogen receptor modulators (SERMs). Two concise syntheses of the SERM raloxifene (Evista®) are presented.

Imidazo[1,2-a]Pyridine-3-Carboxamides Are Active Antimicrobial Agents against Mycobacterium avium Infection In Vivo

ABSTRACT A panel of six imidazo[1,2-a]pyridine-3-carboxamides (IAPs) were shown to have low-micromolar activity against Mycobacterium avium strains. Compound ND-10885 (compound 2) showed significant activity in the lung, spleen, and liver in a mouse M. avium infection model. A combined regimen consisting of ND-10885 (compound 2) and rifampin was additive in its anti-M. avium activity in the lung. Our data indicate that IAPs represent a new class of antibiotics that are active against M. avium and could potentially serve as an effective addition to a combined treatment regimen.

Discovery of selective RIO2 kinase small molecule ligand.

We report the discovery and initial optimization of diphenpyramide and several of its analogs as hRIO2 kinase ligands. One of these analogs is the most selective hRIO2 ligand reported to date. Diphenpyramide is a Cyclooxygenase 1 and 2 inhibitor that was used as an anti-inflammatory agent. The RIO2 kinase affinity of diphenpyramide was discovered by serendipity while profiling of 13 marketed drugs on a large 456 kinase assay panel. The inhibition values also suggested a relative selectivity of diphenpyramide for RIO2 against the other kinases in the panel. Subsequently three available and eight newly synthesized analogs were assayed, one of which showed a 10 fold increased hRIO2 binding affinity. Additionally, this compound shows significantly better selectivity over assayed kinases, when compared to currently known RIO2 inhibitors. As RIO2 is involved in the biosynthesis of the ribosome and cell cycle regulation, our selective ligand may be useful for the delineation of the biological role of this kinase. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.