Kiyoshi Yasui

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.

Inhibitory effect of a TP-receptor antagonist, S-1452, on antigen-induced nasal plasma exudation in guinea pig model for allergic rhinitis.

S-1452, a selective thromboxane (Tx) A2 receptor (TP-receptor) antagonist, was evaluated in antigen- and U-46619 (a TxA2 mimetic)-induced guinea pig nasal plasma exudation models. Exposure of the nasal cavity of actively sensitized guinea pigs to aerosolized ovalbumin (OA) caused marked exudation of dye into both the nasal mucosa and nasal airway lumen. These responses were significantly inhibited by S-1452 (30 mg/kg, p.o.) as well as an H1-antihistamine, diphenhydramine (5 mg/kg, i.v.). In addition, exposure of the nasal cavity of nonsensitized guinea pigs to aerosolized U-46619 or histamine also resulted in nasal plasma exudation, and S-1452 (1 mg/kg, p.o.) almost completely suppressed the U-46619-induced response but did not affect the histamine-induced one, even at a high dose of 30 mg/kg. These results indicate that TxA2 as well as histamine may play an important role in antigen-induced nasal plasma exudation in guinea pigs, and S-1452 can be expected to be useful for the treatment of allergic rhinitis.

Participation of Neuropeptides in Antigen-Induced Contraction of Guinea Pig Bronchi via NK2 but Not NK1 Receptor Stimulation

We evaluated the contribution of neuropeptides to antigen-induced contractions of isolated bronchi and tracheae of passively sensitized guinea pigs using CP-96345 and SR 48968, specific antagonists of NK1 and NK2 receptors, respectively, in combination with treatment by an antihistaminic and a cysteinyl leukotriene antagonist. SR-48968 but not CP-96345, significantly inhibited the late phase of the bronchial contraction. Phosphoramidon, a neutral endopeptidase inhibitor, tended to potentiate bronchial contraction. Posttreatment with SR-48968 decreased the enhanced contraction induced by the inhibitor as well as the nonenhanced contraction to similar levels of tension. On the other hand, antigen-induced tracheal contraction was not altered by either neuropeptide antagonist. These results suggest that neuropeptides mediate the antigen-induced contractile response of the guinea pig bronchus partly through NK2 receptor stimulation.

Contents Vol. 81, 2008

C. Antoniou, Athens L.Z. Benet, San Francisco, Calif. J.F. Borzelleca, Richmond, Va. A. Breckenridge, London F. Colpaert, Castres G. Coruzzi, Parma S. Dhein, Leipzig J.D. Gardner, St. Louis, Mo. T.L. Goodfriend, Madison, Wisc. L.S. Harris, Richmond, Va. D.P. Henry, Indianapolis, Ind. M. Hirafuji, Ishikari-Tobetsu M.D. Hollenberg, Calgary M. Inui, Yamaguchi L.S. Jacob, Penn Valley, Pa. Y. Kamisaki, Osaka N. Kaplowitz, Los Angeles, Calif. A. Kappas, New York, N.Y. K.H. Ko, Seoul W. Kromer, Konstanz A. Levitzki, Jerusalem B.R. Lucchesi, Ann Arbor, Mich. W.E. Müller, Frankfurt am Main T. Narahashi, Chicago, Ill. N.H. Neff , Columbus, Ohio K. Pennypacker, Tampa, Fla. H. Sasaki, Sendai C. Scarpignato, Parma K.-F. Sewing, Hannover K. Starke, Freiburg E. Taira, Iwate K. Takeuchi, Kyoto K. Taniyama, Nagasaki A. Tenenhouse, Montreal P.A. van Zwieten, Amsterdam D.J. Waxman, Boston, Mass. S.J. Yaff e, Bethesda, Md. C. Zeng, Chongqing City International Journal of Experimental and Clinical Pharmacology