title: Synthesis and biological evaluation of novel orally available 1-phenyl-6-aminouracils containing dimethyldihydrobenzofuranol structure for the treatment of allergic skin diseases.
abstract: We have designed and efficiently synthesized novel 1-phenyl-6-aminouracils by replacing the chroman moiety in CX-659S, a nonsteroidal dermatologic candidate, with dimethyldihydrobenzofuranol to cancel CX-659S asymmetric center. Medicinal chemistry effort culminated in the discovery of 13d bearing a 3-methyl group at the 1-phenyl group as a promising compound. Compound 13d, having good in vitro ADME profile and moderate oral bioavailability in mice, showed potent anti-inflammatory activity against hapten-induced contact hypersensitivity reaction in mice following topical and oral administration. The effects of 13d were equipotent to that of tacrolimus or prednisolone. In addition, compound 13d, having potent hydroxyl radical-scavenging activity, showed more potent suppressive effect on substance P-induced pruritus in mice than oxatomide.
authors.affiliation: Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki, Suita, Osaka 564-0053, Japan. Electronic address: tobe-opir@jpma.or.jp.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tobe
authors.affiliation: Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tsuboi
authors.affiliation: Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan. Electronic address: futoshi-hasegawa@ds-pharma.co.jp.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Hasegawa
authors.affiliation: Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Fujiwara
authors.affiliation: Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Isobe
authors.affiliation: Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki, Suita, Osaka 564-0053, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Isobe
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001572:Benzofurans / Q000737:chemistry; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000473:pathology; D006207:Half-Life; D006801:Humans; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D011537:Pruritus / Q000188:drug therapy; D051381:Rats; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D001572:Benzofurans; D014498:Uracil; C013400:6-aminouracil; C105430:benzofuran; C418807:CX 659S
keywords: 1-Phenyl-6-aminouracils; CX-659S; Contact hypersensitivity reaction; Dimethyldihydrobenzofuranol; Pruritus