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The structure of this compound, which is in fact involved in a variety of biochemical processes, comprises a modi ed indole, that is, a benzene ring fused to a nitrogen-containing, ve-membered ring Based on this premise, chemists at Merck prepared a series of compounds that incorporated a serotonin-like fragment in the hope of nding an antagonist that t a putative serotonin site involved in in ammation They were rewarded by nding that an analog from that program had outstanding anti-in ammatory activity in their animal models This compound, indomethacin,10 went on to become a very successful and widely used drug (Fig 5) The mechanism by which it reduced in ammation, it turned out later, had little if anything to do with serotonin.

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randomly perturbing (in the form of random rounding) all calculations This approach is more widely applicable than formal analysis (which can be practically impossible to apply to complex problems) Even where formal analysis is possible, Parker et al show that MCA can also yield tighter practical bounds They argue that this is a very successful idiot light for numerical inaccuracy 4322 Perturbations and Measurement Error Perturbations can be considered in a manner similar to measurement error The effects of measurement error on statistical models have been known for quite some time in a number of contexts (Wald 1940; Nair and Banerjee 1942; Reiersol 1950; Durbin 1954; Madansky 1959) and are well-studied today (Fedorov 1974; Schneeweiss 1976; Fuller 1987, 1990; Stefanski 1989; Wong 1989; Gleser 1992; Cragg 1994; Carrol et al.

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Continued research that involved further modi cation of the structure revealed that good activity was maintained in a related compound in which the nitrogen in the ve-membered ring was replaced by carbon That compound, sulindac,11 also became a very successful drug More detailed pharmacology showed that most of the activity of this compound was in fact due to a metabolite rather than sulindac itself The number of such cases that have already been discussed almost invariably involved oxidation of the rst administered compound In this case, however, the more potent species is generated by a reduction reaction that removes oxygen12 The ensuing years saw the introduction of a very large number of NSAIDs that included acetic acid side chains These drugs all showed similar activity as anti-in ammatory agents, although they varied in potency and duration of action.

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The pattern of side effects, particularly the propensity to cause stomach ulcers, was also quite similar One of the rst series of follow-on compounds came from the nding from the laboratories of MacNeill that the benzene ring fused onto the ve-membered ring in indomethacin could be omitted (Fig 6) The acetic acid side chain in both tolmetin13 and its close relative zomepirac14 is attached directly to an isolated ve-membered, nitrogen-containing pyrrole ring, a so-called heterocycle The benzene ring is still present, but is no longer fused to the ve-membered ring The NSAID clopirac,15 which is available in Europe, represents a further simpli cation yet The acetic acid side chain in yet another NSAID, fentiazac,16 is attached to a ve-membered thiazole ring that includes sulfur in addition to nitrogen.

Chemists in the laboratories of the Boots company where ibufenac had originated continued to prepare additional derivatives of that compound spurred by the very promising activity of this drug17 What again looks like a very minor change led not only to a very successful drug, but also to a class of compounds that all.

1995, 1999; Jaccard and Wan 1995; Buonaccorsi 1996; Schmidt and Hunter 1996; Sutradhar and Rao 1996; Zhao and Lee 1996; Gelfand et al 1997; Lewbel 1997; Mukhopadhyay 1997; Wang and Wang 1997; DeShon 1998; Li and Vuong 1998; Marais and Wecker 1998; Skinner 1998; Cheng and Van Ness 1999; Iturria et al 1999) Essentially there are two problems: zero and nonzero mean measurement error The nonzero case leads obviously and immediately to biased coef cients in the opposite direction of the data bias That is, in a linear model, multiplying some nontrivial > 1 to every case of an explanatory variable, X, implies that larger increases in this variable are required to provide the same effect on the outcome variable, thus reducing the magnitude of the coef cient estimate Another way of thinking about this is that a 1-unit change in X now has a smaller expected change in Y.

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