Synthesis of deuterium labelled pharmaceutical compounds with improved efficacy

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Organic synthesis involves making carbon-based complex molecules from simple ones, just as Lego blocks areclicked together to form large educational and playful structures. Methods for synthesis have advanced andmultiplied so that today we can make complicated molecules, some of which provide medicines andagricultural agents for the benefit of humankind. Today, a very active area, especially in industrial laboratories,is the synthesis of deuterium (D)-containing pharmaceuticals. The replacement of hydrogen (H) of a given drugwith D results in modification/retardation of metabolic fate and alters the therapeutic profile while retaining thebiological potency of the non-D molecules. Thus, the development of D-analogues of currently approvedpharmaceuticals could lead to a positive impact on the safety, efficacy and tolerability of these drugs,addressing important but unmet medical needs. This proposal aims to address these needs by the synthesis of aseries of D-analogues of currently significant marketed drugs. The proposed research is based on ourconsiderable experience in the discovery and development of directed ortho metalation (DoM) and relatedtechnologies for the preparation of aromatic and heteroaromatic molecules. These classes of molecules are themainstay of pharmaceuticals (80% of modern drugs) and are used by industry (e.g. Monsanto, Pfizer, BMS,Merck) for the multi-kg synthesis of marketed pharmaceuticals. We also have a strong knowledge base on thepreparation of D-molecules since this is the backbone reaction of our DoM synthetic strategies. Based on thisbackground and experience, our goals are: a) to incorporate D into commercially available drugs, establishingsynthetic feasibility; b) to develop fundamentally new synthetic steps for introduction of D at early or lateintermediate stages; and c) to develop new routes that truncate known procedures. We anticipate that theresearch will provide Sussex Research an advantage over non-Canadian competitors, and thereby will have apositive impact on the Canadian economy as well as train highly qualified scientists for the Canadian labourmarket.