title: Synthesis and biological activity of various derivatives of a novel class of potent, selective, and orally active prostaglandin D2 receptor antagonists. 2. 6,6-Dimethylbicyclo[3.1.1]heptane derivatives.
abstract: In an earlier paper, we reported that novel prostaglandin D(2) (PGD(2)) receptor antagonists having the bicyclo[2.2.1]heptane ring system as a prostaglandin skeleton were a potent new class of antiallergic agents and suppressed various allergic inflammatory responses such as those observed in conjunctivitis and asthma models. In the present study, we synthesized PGD(2) receptor antagonists having the 6,6-dimethylbicyclo[3.1.1]heptane ring system. These derivatives have the amide moiety, in contrast to those with the bicyclo[2.2.1]heptane ring system, which have the sulfonamide group. The derivatives having the 6,6-dimethylbicyclo[3.1.1]heptane ring also exhibited strong activity in PGD(2) receptor binding and cAMP formation assays. In in vivo assays such as allergic rhinitis, conjunctivitis, and asthma models, these series of derivatives showed excellent pharmacological profiles. In particular, compound 45 also effectively suppressed eosinophil infiltration in allergic rhinitis and asthma models. This compound (45, S-5751) is now being developed as a promising alternative antiallergic drug candidate.
authors.affiliation: Shionogi Research Laboratories, Shionogi & Co., Ltd., 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Mitsumori
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Tsuri
authors.forename: Tsunetoshi
authors.initials: T
authors.lastname: Honma
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Hiramatsu
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Okada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hashizume
authors.forename: Shiro
authors.initials: S
authors.lastname: Kida
authors.forename: Masanao
authors.initials: M
authors.lastname: Inagaki
authors.forename: Akinori
authors.initials: A
authors.lastname: Arimura
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yasui
authors.forename: Fujio
authors.initials: F
authors.lastname: Asanuma
authors.forename: Junji
authors.initials: J
authors.lastname: Kishino
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohtani
mesh_terms: D000284:Administration, Oral; D000402:Airway Obstruction / Q000188:drug therapy / Q000276:immunology; D000818:Animals; D018926:Anti-Allergic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D003228:Conjunctiva / Q000098:blood supply; D000242:Cyclic AMP / Q000096:biosynthesis; D004804:Eosinophils / Q000473:pathology; D006168:Guinea Pigs; D006536:Heptanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015230:Prostaglandin D2 / Q000378:metabolism*; D011869:Radioligand Assay; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D012221:Rhinitis, Allergic, Perennial / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C432167:7(2-(5-hydroxybenzo(b)thiophen-3-ylcarbonylamino)-10-norpinan-3-yl)hept-5-enoic acid; D018926:Anti-Allergic Agents; D001643:Bridged Bicyclo Compounds; D006536:Heptanes; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013876:Thiophenes; D000242:Cyclic AMP; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor