Discovery of N-sulfonyl-7-azaindoline derivatives as potent, orally available and selective M4 muscarinic acetylcholine receptor agonists

We designed and synthesized novel N-sulfony1-7-azaindoline derivatives as selective M-4 muscarinic acetylcholine receptor agonists. Modification of the N-carbethoxy piperidine moiety of compound 2, an M-4 muscarinic acetylcholine receptor (mAChR)-preferring agonist, led to compound I, a selective M-4 mAChR agonist. Compound 1 showed a highly selective M-4 mAChR agonistic activity with weak hERG inhibition in vitro. A pharmacokinetic study of compound 1 in vivo revealed good bioavailability and brain penetration in rats. Compound 1 reversed methamphetamine-induced locomotor hyperactivity in rats (1-10 mg/kg, po). (C) 2014 Elsevier Ltd. All rights reserved.