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Fig. 11 Non-peptidyl phosphorus PTP inhibitor leads ray structure of PTP1B in complex with compound 18 (difluoro-naphthalen-2-yl-methyl)-phosphonic acid (Burke et al. 1996b; Ye and Burke 1996). Based on this structure, it was hypothesized that the addition of a hydroxyl group at the 4-position of the naphthyl ring could replace a water molecule and thereby allow H-bond formation to Tyr46 and Lys120. Indeed, addition of this hydroxyl group increased the affinity twofold, i.e., structure-based design of non-peptide PTP inhibitors was born. Further development of this concept was leading to compounds with Ki values in the low micromolar range [(Groves et al. 1998) pdb code1BZC].

At Merck-Frosst these studies were extended, and it was found that introduction of two difluoromethylenephosphonic (DFMP) groups into naphthalene-based compounds significantly increased the potency against PTP1B (Wang et al. 1998). For the first time it was demonstrated that selectivity could be obtained by different, simple substitutions. Thus, within this series one compound (22) was five- to sixfold more potent against PTP1B (Ki=16 mM) than CD45 and another compound (23) showed a fivefold preference for CD45 (Ki=9 mM) over PTP1B. Further elaborations on this approach led Zhang et al. to develop a highly selective PTP1B inhibitor with similar potency as compound 22, i.e., Ki~1 mM (Taing et al. 1999).

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