Synthesis of halogenated trimetoquinol derivatives and evaluation of their β-agonist and thromboxane A2 (TXA2) antagonist activities

Article abstract of DOI:10.1021/jm00081a007

The 5,8-difluoro (4), 5-iodo (5), 8-iodo (6), and 5-trifluoromethyl (7) derivatives of trimetoquinol (TMQ, 1) have been synthesized and evaluated for their ability to stimulate β₁ (guinea pig atria) and β₂ (guinea pig trachea) adrenoceptors as well as for their inhibitory activity against U46619 [a thromboxane A₂ (TXA₂) mimetic]-mediated contraction of rat thoracic aorta and human platelet aggregation. Both 5 and 6 were considerably less active than TMQ on both β-adrenergic systems and gave a rank order of stimulatory potency of 1 >> 6 ≥ 5. Similarly, iodine substitution at either position also caused a reduction in TXA₂ antagonist activity with a rank order potency of 1 > 6 >> 5. Compared to 1, however, 5-iodo-TMQ (5) showed a marked selectivity for blockade of U46619 responses in rat aorta over human platelets. On β-systems, 4 had reduced potency compared to TMQ and was similarly nonselective. Introduction of a trifluoromethyl group at the 5- position of TMQ completely abolished both β₁- and β₂-adrenergic agonist activities while imparting weak antagonist activity on β₁ receptors. On TXA₂ systems, both 4 and 7 possessed significantly decreased inhibitory activity compared to TMQ. The synthetic approaches to the synthesis of 8- (trifluoromethyl)-TMQ (8) are also described. The enantiomers of the 8-fluoro derivative (3) of TMQ were separated on a preparative Chiralcel OD column and evaluated on β-adrenergic systems and TXA₂ systems. On β-adrenergic systems, (S)-(+)-8-fluoro-TMQ was at least 10-fold more potent than (R)-(-)- 8-fluoro-TMQ. Conversely, (R)-(-)-8-fluoro-TMQ was approximately 14-fold more potent as an antagonist of TXA₂-mediated aggregation in human platelets than (S)-(+)-8-fluoro-TMQ. In contrast to platelets, (S)-(+)-8-fluoro-TMQ was an agonist in rat aorta whereas (R)-(-)-8-fluoro-TMQ was an antagonist.