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.
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.
Mitsumori
Susumu
S
Shionogi Research Laboratories, Shionogi & Co., Ltd., 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan.
Tsuri
Tatsuo
T
Honma
Tsunetoshi
T
Hiramatsu
Yoshiharu
Y
Okada
Toshihiko
T
Hashizume
Hiroshi
H
Kida
Shiro
S
Inagaki
Masanao
M
Arimura
Akinori
A
Yasui
Kiyoshi
K
Asanuma
Fujio
F
Kishino
Junji
J
Ohtani
Mitsuaki
M
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
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