Discovery of N-sulfonyl-7-azaindoline derivatives as potent, orally available and selective M(4) muscarinic acetylcholine receptor agonists.
We designed and synthesized novel N-sulfonyl-7-azaindoline derivatives as selective M4 muscarinic acetylcholine receptor agonists. Modification of the N-carbethoxy piperidine moiety of compound 2, an M4 muscarinic acetylcholine receptor (mAChR)-preferring agonist, led to compound 1, a selective M4 mAChR agonist. Compound 1 showed a highly selective M4 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).
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
Atsushi
A
Suwa
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
Yasuko
Y
Konishi
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
Yoshiharu
Y
Uruno
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
Kentaro
K
Takai
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
Tomokazu
T
Nakako
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
Mutsuko
M
Sakai
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
Takeshi
T
Enomoto
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
Yoshiaki
Y
Ochi
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
Harumi
H
Matsuda
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
Atsushi
A
Kitamura
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
Yasuaki
Y
Uematsu
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
Akihiko
A
Kiyoshi
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan. Electronic address: t-sumiyo@kansai-u.ac.jp.
Takaaki
T
Sumiyoshi
D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008694:Methamphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D043588:Receptor, Muscarinic M4 / Q000819:agonists*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
D010880:Piperidines; D043588:Receptor, Muscarinic M4; D013449:Sulfonamides; D008694:Methamphetamine
M(4) muscarinic acetylcholine receptor; Muscarinic acetylcholine receptor agonist; N-Sulfonyl-7-azaindoline; Schizophrenia; Subtype-selective agonist