Harry Finch completed his PhDin organic chemistry at Manchester University, UKin 1975. Hehas worked at Ciba-Geigy, Roche, Allen &Hanbury’s, andGlaxoWellcome where he became Director of Chemistry.He has worked across a range of therapeutic areas and at several biotechnology companies and is currentlyan executive director of Pulmagen Therapeutics, and a non-executive Director of both C4X Discovery Ltd and Pulmocide Ltd.Heis co-inventor of the widely prescribed respiratory medicine serevent and has associations with multiple other drugs in clinical and pre-clinical evaluation (respiratory and oncology).
Highly selective Orexin-1 (OX1) antagonists have demonstrated pre-clinical proof of concept for ameliorating a range of reward-related disorders as well as alcohol and substance abuse. Here we present results from our in-house OX1 program, demonstrating how free ligand 3D-structures of available selective and non-selective antagonists were determined experimentally from NMR and used in aligand-centric conformational design process that has identified several new series of highly selective antagonists. This procedure guided the definition of a sophisticated pharmacophore model that rationalised literature data and provided a firm structural understanding of OX1 selectivity. De novo design and virtual screening hits from this model identified several highly promising series, with compounds having up to 50x selectivity and activity in the 100nMrange, after one cycle of optimisation. Experimentally determined free solution 3D-structures of these initial hits were used to extract conformational information from both inactive and active molecules as the principal driver for iterative conformational design. Subsequent conformational design iterations enabled the identification of multiple selective series of <10nM potency and >1000x selectivity with suitable properties for in vivo investigation. Furthermore, the understanding of the conformational requirements for selectivity and activity allowed the precise modulation of the scaffold and functional groups in the lead compounds to rapidly address liabilities such as metabolic instability. Experimentally determined solution 3D structural information provide a powerful method of informing structure based drug design in new ways and its application to targeting the protein-protein interaction of Keap-1/Nrf-2 will also be discussed.