LAUSR

An experimental approach is described for late stage lead diversification (LSLD) of frontrunner drug candidates using nanomole scale amounts of lead compounds for SAR development. The process utilizes C-H bond activation methods to explore chemical space by transforming candidates into newly functionalized leads. A key to success is the utilization of micro-cryoprobe NMR spectroscopy which permits the use of low amounts of lead compounds (1-5 μmoles). The approach delivers multiple analogs from a single lead at nanomole scale amounts as DMSO-d6 stock solutions with known structure and concentration for in vitro pharmacology and ADME testing. To demonstrate the feasibility of this approach, we have used the antihistamine agent loratadine (1). Twenty-six analogs of loratadine were isolated and fully characterized by NMR. Informative SAR analogs were identified which display potent affinity for the human histamine H1 receptor and improved metabolic stability.