BAY u3405, a potent and selective thromboxane A₂ receptor antagonist on airway smooth muscle in vitro

Abstract

1 BAY u3405 (3(R)- [[(4-fluorophenyl) sulphonyl]amino]-1,2,3,4-tetrahydro-9H-carbazole-9-propanoic acid) has been evaluated on airway smooth muscle, from a number of species including man, for its thromboxane A2 (TXA2) antagonist activity. 2 BAY u3405 was a potent, and competitive, antagonist of the TXA2-mimetic U46619-induced contractions of human, guinea-pig, rat and ferret airway smooth muscle with pA2 values between 8.0 and 8.9 and with no inherent contractile activity (10 -IO-M). 3 The TXA2 antagonist activity of BAY u3405 was stereoselective. Its (S)-enantiomer, BAY u3406, was approximately 50 fold less effective against U46619 on guinea-pig and human airway smooth muscle. 4 BAY u3405 also competitively antagonized contractions of guinea-pig airway smooth muscle induced by prostaglandin D2 (PGD2) or its metabolite 9a, 1 lfl-PGF2. On human and ferret airway smooth muscle it abolished contractions induced by PGD2, PGF2. and 16, 5 A high concentration (10-6 M) of BAY u3405 had no effect on the contraction, or relaxation, of airway smooth muscle induced by a range of other agonists, nor did BAY u3405 have any effect on other prostanoid receptor types (DP, EP1, EP2, FP or IP). 6 BAY u3405, in contrast to some other TXA2 antagonists, is a potent and selective antagonist on a wide range of airways including human. This high affinity, and the oral activity of the compound described elsewhere, suggest it may be an appropriate tool to investigate the role of prostanoids in airway diseases such as asthma.

Prostaglandin D2 Causes Preferential Induction of Proinflammatory Th2 Cytokine Production through an Action on Chemoattractant Receptor-Like Molecule Expressed on Th2 Cells

“…Ramatroban was developed initially as a potent TP receptor antagonist (20). Recent studies revealed that this drug is also a CRTH2 antagonist and capable of inhibiting CRTH2-mediated eosinophil migration (21).…”

“…Interestingly, PGD 2 alone elicited the production of IL-4, IL-5, and IL-13 by Th2 cells without affecting the production of IL-10. Ramatroban (BAY u 3405), original defined as a thromboxane-like prostanoid receptor (TP) antagonist and recently identified to also be a potent CRTH2 antagonist (20,21), abolished Th2 cell responses to PGD 2 . This inhibition was mediated by CRTH2 because SQ29548, a specific TP antagonist, did not mimic the effect of ramatroban.…”

BAY u3405 an antagonist of thromboxane A2‐ and prostaglandin D2‐induced bronchoconstriction in the guinea‐pig

“…Although the limited activity of GR 32191 may simply reflect low potency, it might alternatively reflect limited activity against all TXA2 receptor subtypes. McKenniff et al (1988McKenniff et al ( , 1991 have suggested that subtypes of TXA2 receptors exist in airway smooth muscle. They have demonstrated that some TXA2 antagonists, including GR 32191, were not equipotent at all such subtypes.…”

“…It is possible that high antagonist potency at all TXA2 subtypes is essential for a drug to clarify the role of TXA2 and PGD2 in asthma. It is probable that BAY u3405 is such a drug as it has been shown to have good activity at all TXA2 receptor subtypes (McKenniff et al, 1991).…”

“…BAY u3405 has been shown to be such an antagonist on a wide range of airway preparations in vitro (McKenniff et al, 1991). In In experiments where the test compound was administered by aerosol, an aerosol generator (Devilbiss 'Pulmosonic') was introduced into the system as described by Lees & Payne (1985).…”