title: Discovery of N-substituted 7-azaindoline derivatives as potent, orally available M1 and M4 muscarinic acetylcholine receptors selective agonists.
abstract: We designed and synthesized novel N-substituted 7-azaindoline derivatives as selective M1 and M4 muscarinic acetylcholine receptors (mAChRs) agonists. Hybridization of compound 2 with the HTS hit compound 5 followed by optimization of the N-substituents of 7-azaindoline led to identification of compound 1, which showed highly selective M1 and M4 mAChRs agonistic activity, weak human ether-a-go-go related gene inhibition, and good bioavailability in multiple animal species.
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takai
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Yasunao
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Konishi
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suwa
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Uruno
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Matsuda
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Nakako
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Sakai
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishikawa
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Gakuji
authors.initials: G
authors.lastname: Hashimoto
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Enomoto
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kitamura
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Uematsu
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kiyoshi
authors.affiliation: 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.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sumiyoshi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D000882:Haplorhini; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D043588:Receptor, Muscarinic M4 / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D043588:Receptor, Muscarinic M4
keywords: 7-Azaindoline derivative; Antipsychotic agents; M(1) muscarinic acetylcholine receptor; M(4) muscarinic acetylcholine receptor; Schizophrenia; Subtype-selective agonist