Discovery and Development of 3‑(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane Hydrochloride (SUVN-911): A Novel, Potent, Selective, and Orally Active Neuronal Nicotinic Acetylcholine α4β2 Receptor Antagonist for the Treatment of Depression

A series of chemical
optimizations guided by in vitro affinity
at the α4β2 receptor in combination with selectivity against
the α3β4 receptor, pharmacokinetic evaluation, and in
vivo efficacy in a forced swim test resulted in identification of
3-(6-chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]­hexane hydrochloride
(9h, SUVN-911) as a clinical candidate. Compound 9h is a potent α4β2 receptor ligand with a Ki value of 1.5 nM. It showed >10 μM
binding
affinity toward the ganglionic α3β4 receptor apart from
showing selectivity over 70 other targets. It is orally bioavailable
and showed good brain penetration in rats. Marked antidepressant activity
and dose-dependent receptor occupancy in rats support its potential
therapeutic utility in the treatment of depression. It does not affect
the locomotor activity at doses several folds higher than its efficacy
dose. It is devoid of cardiovascular and gastrointestinal side effects.
Successful long-term safety studies in animals and phase-1 evaluation
in healthy humans for safety, tolerability, and pharmacokinetics paved
the way for its further development.