NONPROSTANOID PROSTACYCLIN MIMETICS .4. DERIVATIVES OF 3-[2-(4,5-DIPHENYL-2-OXAZOLYL)ETHYL]PHENOXY]ACETIC ACID SUBSTITUTED-ALPHA TO THE OXAZOLE RING

The 4,5-diphenyloxazole derivatives 2-4 were previously identified as nonprostanoid prostacyclin (PGI(2)) mimetics. A series of derivatives of 2-4 bearing substitutents at the carbon atom cu to the oxazole ring were synthesized and evaluated as inhibitors of ADP-induced aggregati on of human platelets in vitro. In the unsaturated series, the alpha-c arbethoxy derivative 1Oa, evaluated as an equal mixture of geometrical . isomers, inhibited platelet aggregation with an IC50 of 0.36 mu M. E valuation of the individual methyl ester derivatives (E)-9a and (Z)-9a revealed that (E)-9a was 10-fold more potent than (Z)-9a. In the satu rated series, the alpha-carbomethoxy-substituted compound 12a inhibite d platelet aggregation with an IC50 of 0.08 mu M, 15-fold more potent than the unsubstituted prototype 2. The potency of 12a was found to be sensitive to variation of the methoxy moiety. The ethyl (12b) and iso propyl (12d) esters were less effective as were the acid 12e and a ser ies of amides (12f-h). Other substituents introduced at this site of t he pharmacophore included P(O)(OEt)(2) (25), SCH3 (31a), S(O)CH3 (31b) , SO2CH3 (31c), isopropyl (31d), phenyl (31f), and CH2OH (31i). Howeve r, none were significantly more potent inhibitors of platelet function than the parent compound 2. The results indicate the presence of a po cket in the PGI(2) receptor protein that preferentially recognizes sma ll, polar but uncharged substituents. The structure-activity correlate s are suggestive of a hydrogen-bond interaction between a donor moiety on the PGI(2) receptor and the methoxycarbonyl functionality of 12a t hat is sensitive to both the size of the substituent and its stereoche mical presentation in this structural class of PGI(2) mimetic. The eth yl ester 12b dose-dependently displaced [H-3]iloprost from human plate let membranes and stimulated adenylate cyclase. However, the maximal s timulation was less than that recorded for iloprost, indicating that 1 2b functions as a partial agonist at the PGI(2) receptor.