title: Synthesis and biological activity of various derivatives of a novel class of potent, selective, and orally active prostaglandin D2 receptor antagonists. 1. Bicyclo[2.2.1]heptane derivatives.
abstract: Novel prostaglandin D(2) (PGD(2)) receptor antagonists were synthesized as a potential new class of antiallergic agents having a bicyclo[2.2.1]heptane ring system with sulfonamide groups. Some of them exhibit extremely potent antagonism of the PGD(2) receptor in radioligand binding and cAMP formation assays with IC(50) values below 50 nM and much less antagonism of TXA(2) and PGI(2) receptors. These potent PGD(2) receptor antagonists, when given orally, dramatically suppress various allergic inflammatory responses such as increased vascular permeability in allergic rhinitis, conjunctivitis, and asthma models. The excellent pharmacological profiles of PGD(2) receptor antagonists, originally synthesized in our laboratories, are of potentially great clinical significance. This study also provides experimental evidence suggesting that PGD(2) plays an important role in the pathogenesis of allergic diseases.
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: 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; 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; D006168:Guinea Pigs; D006586:Hexanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015230:Prostaglandin D2 / Q000378:metabolism*; D011869:Radioligand Assay; D044006:Receptors, Epoprostenol; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D018926:Anti-Allergic Agents; D001643:Bridged Bicyclo Compounds; D006586:Hexanes; D044006:Receptors, Epoprostenol; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D000242:Cyclic AMP; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor