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Notes: IC50 nM values except; aKi nM values; b% inhibition at 10 ^M. Because of different assay methods care should be taken in making comparisons between the results from different research groups.

Notes: IC50 nM values except; aKi nM values; b% inhibition at 10 ^M. Because of different assay methods care should be taken in making comparisons between the results from different research groups.

as SC44463 (1; Searle), are particularly potent in terms of their in vitro activity (48). Indeed, the hydroxamic acid group has proved to be a particularly effective ZBG, and the majority of inhibitors currently in clinical testing contain this group. Recent X-ray crystallography studies have shown that the hydroxamate acts as a bidentate ligand, with each oxygen an optimal distance (1.9-2.3 A) from the active-site zinc(II) ion, and the position of the hydroxamate nitrogen suggests that it is protonated and forms a hydrogen bond with a carbonyl oxygen of the enzyme backbone of neutrophil collagenase (54,57,59), fibroblast collagenase (56), matrilysin (58), and stromelysin-1 (60,61,63). Investigations of the SAR for RHS inhibitors, such as 1 and analogs, has been extensively reviewed (43,48), and led to the discovery of important prototype inhibitors Galardin™ (2; Glycomed) (68), Batimastat® (3; British Biotech; 69,70), and analogs (e.g., 4; BB-1101 British Biotech). These compounds show broad specificity in their inhibition of the members of the MMP family, but display little detectable activity against other classes of metalloproteinases, such as angiotensin converting enzyme and enkephalinase (68). It is of interest to note that the screening of natural products has led to the discovery of structurally related MMP inhibitors, namely actinonin (5; Rhone-Poulenc; 71), BE16627B (6; Banyu; 72), matlystatin B (7; Sankyo; 73), and YM-24074 (8; Yamanonchi; 74). Systematic structural modifications to the pseudopeptide hydroxamic acid derivatives resulted in two key discoveries. The first, made by workers at Celltech, was that a degree of enzyme selectivity could be obtained; particularly, that the introduction of larger P1' substituents (e.g., the 3-phenylpropyl P1' substituent in 9 and 10) enhances inhibition of the gelatinases and stromelysin-1, at the expense of activity against fibroblast collagenase and matrilysin (42,75). The second was made by the group at British Biotech, who discovered that the combination of certain substituents gave orally active broad spectrum compounds (43). Previous work from the groups at Sterling Winthrop and Celltech had shown that the introduction of basic substituents at P3' increased plasma half-life, and enhanced oral activity (76,77). The British Biotech group found that the combination of an a-hydroxy group with tert-butylglycine at P2', as in Marimastat 11, was particularly advantageous. The precise reasons for Marimastat's improved bioavailability are not clear, but the substitutions made may reduce the compound's susceptibility to peptidases, improve absorption, or reduce first-pass metabolism (43). Recent results from Kanebo indicate that a P2' phenylglycine substituent (e.g., 12) can also lead to oral activity (78).

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