Abstract: Gamma aminobutyric acid receptors (GABAAR) have been targeted for CNS indication for more sixty years with the identification of GABA in the brain by Eugene Roberts in 1950 and the discovery of Librium by Leo Sternbach (Hofman-La Roche) in 1955. In 1975, Haefely found that GABA is involved in the action of benzodiazepines and in 1987 Barnard and Seeburg cloned several GABAA receptor subunits for the first time. The pentameric chloride ion channel is made up of 19 known subunits with the α1-3β2γ2 combination being the most abundant in the brain. Prompted by multiple reports demonstrating the expression of GABAARs on non-neuronal cells, our group started to develop small molecules that target GABAARs outside the brain. Our collaborator, Prof. Emala at Columbia University demonstrated the expression of GABAARs on airway smooth muscle cells, which led us to the development of new drug candidates for asthma that relax constricted airways and reduce lung inflammation. One compound (MIDD0301 or PI301) is of important interest, because of its strong interaction with GABAARs and inability to cross the blood brain barrier. Experiments have shown that low permeability and fast phase 2 metabolism are responsible for this attribute. Importantly, we have shown that the phase 2 metabolites of MIDD0301 still bind GABAARs. In addition, to the comprehensive pre-clinical characterization of PI301 that include pharmacokinetic and pharmacodynamic studies, the presentation will highlight some interesting aspects of the synthesis and physiochemical properties of MIDD0301. The presentation of related compounds will demonstrate different approaches to control tissue selectivity and improve the impurity profile for large scale synthesis. The presentation includes aspects of chemistry, analytical chemistry, biochemistry, pharmacology, and drug discovery and development.
Bio: Prof. Arnold received his PhD under Nobel Laureate Ben Feringa in organic chemistry in 2002. He expanded his knowledge in biochemistry and molecular biology at UC San Francisco as postdoctoral researcher under the leadership of Dr. Kip Guy, who is currently the Dean of the ÌÇÐÄvlog¹Ù·½Èë¿Ú College of Pharmacy. In 2005, the Guy research group including Dr. Arnold moved to Memphis and established the Department of Chemical Biology and Therapeutics at St. Jude Children’s Research Hospital. Dr. Arnold’s tasks included the development and execution of high throughput screens, parallel compound library synthesis, development of secondary assays for validation of compound activities, identification of lead compounds, and preclinical profiling of drug candidates. At the University of Wisconsin-Milwaukee, Dr. Arnold quickly advanced as an expert in the field of vitamin D research and developed new potent anti-tumor agents for ovarian cancer and leukemia. He also collaborated with Prof. Cook and characterized new drug candidates for asthma, schizophrenia, and neuropathic pain. Together with Dr. Stafford, he established Pantherics Incorporated in 2017 and became the Director of the Milwaukee Institute for Drug Discovery in 2021. The institute comprises five specialty laboratories supporting drug discovery and drug development at UWM.