Late Stage Lead Diversification (LSLD) Coupled with Quantitative NMR Spectroscopy to Identify New SAR Vectors at Nanomole Scale Synthesis: Application to Loratadine a Human Histamine H 1 Receptor Inverse Agonist.

An experimental approach is described for late-stage lead diversification of frontrunner drug candidates using nanomole-scale amounts of lead compounds for structure-activity relationship 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 microcryoprobe nuclear magnetic resonance (NMR) spectroscopy, which permits the use of low amounts of lead compounds (1-5 mu mol). The approach delivers multiple analogues from a single lead at nanomole-scale amounts as DMSO-d(6) stock solutions with a known structure and concentration for in vitro pharmacology and absorption, distribution, metabolism, and excretion testing. To demonstrate the feasibility of this approach, we have used the antihistamine agent loratadine (1). Twenty-six analogues of loratadine were isolated and fully characterized by NMR. Informative SAR analogues were identified, which display potent affinity for the human histamine H-1 receptor and improved metabolic stability.