The recent discovery of an alternative form cyclooxygenase (cyclooxygenase-2, COX-2), which has been proposed to play a significant role in inflammatory conditions, may provide an opportunity to develop anti-inflammatory drugs with fewer side effects than existing non-steroidal anti-inflammatory drugs (NSAIDs). We have now identified 6-[(2,4-difluorophenyl)-thio]-5-methanesulfonamido-1-indanone++ + (20) (L-745,337) as a potent, selective, and orally active COX-2 inhibitor. The structure-activity relationships in this series have been extensively studied. Ortho- and para-substituted 6-phenyl substitutents are optimal for in vitro potency. Replacement of this phenyl ring by a variety of heterocycles gave compounds that were less active. The methanesulfonamido group seems to be the optimal group at the 5-position of the indanone system. Compound 20 has an efficacy profile that is superior or comparable to that of the nonselective COX inhibitor indomethacin in animal models of inflammation, pain, and fever and appears to be nonulcerogenic within the dosage ranges required for functional efficacy. Although 20 and its oxygen linkage analog 2 (flosulide) are equipotent in the in vitro assays, compound 20 is more potent in the rat paw edema assay, has a longer t1/2 in squirrel monkeys, and seems less ulcergenic than 2 in rats.

The enantiomers of the leukotriene D4 antagonist 3-[[[3-[2-(7-chloroquinolin-2-yl)-(E)-ethenyl]phenyl] [[3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]propionic acid (L-660,711)(MK-571) have been prepared, their absolute stereochemistry has been assigned as S for (+)-1 and R for (-)-1 by X-ray analysis of a synthetic intermediate (5), and the biological activity of the enantiomers has been explored. Unexpectedly, the enantiomers are both comparably biologically active with (+)-1 slightly more intrinsically active at the LTD4 receptor in vitro.

1573may occur in other drug-receptor systems. For example, opioid phenylmorphans and 3-phenyl-and 4-phenylpiperidines also form such pair^.^^^^"^ A possible molecular explanation for the opposite activity of enantiomers may be the delocalization of charge that occurs when amines are p r o t~n a t e d .~~ That is, rather than being concentrated on the ammonium hydrogen, the positive charge is spread over the adjacent C-N bonds so that the "back" of the N-H bond also contains significant positive charge. Thus, (6aS)-NPA may be able to bind to the same receptor site as (6aR)-NPA since the overall shapes of these molecules are similar and there is sufficient charge at the back of the N-H bond to allow binding to a complementary electrostatic site in the receptor. Antagonists may bind to the same receptor site as agonists, but it appears that agonist activity requires the proper N-H orientation.To summarize, two ((6aS)-NPA and (lS,2R)-5-OH-MDAT) of the three postsynaptic DA antagonists can be closely superimposed with the juxtaposition of the phenyl m-hydroxyl, the N-substituent, and the direction of the N-H bond. The third antagonist, (3S)-PPP, can also assume this conformation with only a moderate energy penalty possibly accounting for its relatively low potency.A similar juxtaposition occurs for the three DA agonists.These observations point out the importance of the orientation of the ammonium hydrogen (or lone-pair electrons) in determining agonist and antagonist activity at DA receptors. This view is consistent with a previous proposal17 that the 6a-hydrogen at the chiral center of aporphines is responsible for the enantiomeric selectivity of such aporphines since the chiral center also determines the orientation of the ammonium hydrogen.Acknowledgment. Dr. Yvonne Martin of Abbott Laboratories provided valuable discussions. This work was supported by the following USPHS grants and awards: RRO5484 (to M.F.) from the National Biomedical Research Program of the NIH, (NINCDS) NS-15439 (to J.L.N.), and (NIMH) MH-47370 and MH-34006 (to R.J.B.). Reamer, M.; Nickander, R. In Problems of Drug Dependence 1981; Harris, L. S., Ed.; NIDA Research Monograph 41: Rockville, MD, 1982; pp 112-118. (46) Awaya, H.; May, E. L.; Aceto, M. D.; Merz, H.; Rogers, M. E.; Harris, L. S. J. Med. Chem. 1984,27, 536-539. (47) Cheng, A.; Uyeno, E.; Polgar, W.; Toll, L.; Lawson, J. A.; De-Graw, J. I.; Loew, G.; Camerman, A.; Camerman, N.