title: Identification of 2,3-disubstituted pyridines as potent, non-emetic PDE4 inhibitors.
abstract: A series of 2,3-disubstituted pyridines were synthesized as potential non-emetic PDE4 inhibitors. To decrease brain exposure and minimize emesis, we modified the lipophilic moiety of a series of emetic PDE4 inhibitors and found that introduction of a hydroxy group into the pyridine moiety of the side chain led to non-emetic compounds with preserved PDE4 inhibitory activity. Following optimization at the phenoxy group, we identified compound 1 as a potent non-emetic PDE4 inhibitor. Compound 1 showed significant efficacy in an animal model of asthma without inducing emesis.
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Motoji
authors.initials: M
authors.lastname: Kawasaki
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan. Electronic address: akira-fusano@ds-pharma.co.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Fusano
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nigo
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Shunya
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Mari N
authors.initials: MN
authors.lastname: Ito
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Teranishi
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Toda
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Naruaki
authors.initials: N
authors.lastname: Nomura
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan. Electronic address: t-sumiyo@kansai-u.ac.jp.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sumiyoshi
mesh_terms: D000284:Administration, Oral; D001249:Asthma / Q000188:drug therapy*; D004639:Emetics / Q000009:adverse effects; D004789:Enzyme Activation / Q000187:drug effects; D015394:Molecular Structure; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004639:Emetics; D058988:Phosphodiesterase 4 Inhibitors; D011725:Pyridines; C023666:pyridine
keywords: 2,3-Disubstituted pyridine; Anti-inflammatory agent; PDE4 inhibitors; Phosphodiesterase 4; Structure activity relationship