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

Susumu Mitsumori; Tatsuo Tsuri; Tsunetoshi Honma; Yoshiharu Hiramatsu; Toshihiko Okada; Hiroshi Hashizume; Shiro Kida; Masanao Inagaki; Akinori Arimura; Kiyoshi Yasui; Fujio Asanuma; Junji Kishino; Mitsuaki Ohtani

doi:10.1021/jm0205189

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

J Med Chem. 2003 Jun 5;46(12):2446-55. doi: 10.1021/jm0205189.

Authors

Susumu Mitsumori¹, Tatsuo Tsuri, Tsunetoshi Honma, Yoshiharu Hiramatsu, Toshihiko Okada, Hiroshi Hashizume, Shiro Kida, Masanao Inagaki, Akinori Arimura, Kiyoshi Yasui, Fujio Asanuma, Junji Kishino, Mitsuaki Ohtani

Affiliation

¹ Shionogi Research Laboratories, Shionogi & Co., Ltd., 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan.

PMID: 12773048
DOI: 10.1021/jm0205189

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.

MeSH terms

Administration, Oral
Airway Obstruction / drug therapy
Airway Obstruction / immunology
Animals
Anti-Allergic Agents / chemical synthesis*
Anti-Allergic Agents / chemistry
Anti-Allergic Agents / pharmacology
Asthma / drug therapy
Asthma / immunology
Asthma / pathology
Blood Platelets / drug effects
Blood Platelets / metabolism
Bridged Bicyclo Compounds / chemical synthesis*
Bridged Bicyclo Compounds / chemistry
Bridged Bicyclo Compounds / pharmacology
Capillary Permeability / drug effects
Conjunctiva / blood supply
Cyclic AMP / biosynthesis
Eosinophils / pathology
Guinea Pigs
Heptanes / chemical synthesis*
Heptanes / chemistry
Heptanes / pharmacology
Humans
Prostaglandin D2 / metabolism*
Radioligand Assay
Receptors, Immunologic*
Receptors, Prostaglandin / antagonists & inhibitors*
Rhinitis, Allergic, Perennial / drug therapy
Rhinitis, Allergic, Perennial / immunology
Rhinitis, Allergic, Perennial / pathology
Stereoisomerism
Structure-Activity Relationship
Thiophenes / chemical synthesis*
Thiophenes / chemistry
Thiophenes / pharmacology

Substances

7(2-(5-hydroxybenzo(b)thiophen-3-ylcarbonylamino)-10-norpinan-3-yl)hept-5-enoic acid
Anti-Allergic Agents
Bridged Bicyclo Compounds
Heptanes
Receptors, Immunologic
Receptors, Prostaglandin
Thiophenes
Cyclic AMP
Prostaglandin D2
prostaglandin D2 receptor