Conformation of gem-disubstituted alkylarylpiperidines and their implication in design and synthesis of a conformationally-rigidified NK1 antagonist

Abstract Piperidines are ubiquitous in pharmaceuticals and bioactive natural products. Understanding the structural and functional properties of piperidines plays a key role in drug design and development. This Letter reported studies of conformation of a set of gem -disubstituted methylphenylpiperidines in the context of discovery of NK 1 antagonists. The findings led to re-design and an efficient synthesis of a potent NK 1 antagonist with excellent in vivo activity and rodent and monkey pharmacokinetic profiles.