groups also searched for orally active drugs with mechanisms of action different from the inhibitors just described. At Zeneca, this work was begun in the late 1980s where "active-site-directed" inhibitors were designed to fit 5-K) selectively without the need for redox or strong iron ligand properties. This was particularly difficult in the absence of structural data on 5-LO; however, based on the hypothetical mechanism discussed in Section 5.1.1,
which implies the presence of an Fe atom and a basic group adjacent to a lipophilic pocket in the active site, lipophilic imidazoles were initially synthesized to interact with these structural elements.
It was discovered that replacement of the imidazole by a thiazole and introduction of confonnational restriction with rnethoxy and alkyl groups gave the in vitro potent ZM211965 (11) (ICgo = 0.1 vM, guinea pig 5-LO; IC50 = 0.4 ¡xM, human whole blood LTB4 inhibition) that importantly showed no
COX-1 inhibition up to 100 yM in human blood (152, 153). Cyclic voltammetry and iron chelation measurements confirmed that this (methoxyalkyl)thiazole series is free from redox and iron-complexing properties. The series differs from redox and the iV-hydroxyurea series in that it demonstrates enantioselective inhibition of 5-LO both in vitro and in vivo (154). This was the first evidence of 5-LO inhibitors forming enantiospecific interactions with the enzyme. Thus, unlike the a-methylene center in the Abbott N-hydroxyurea series, the stereoselectivity of these ligands indicates a close contact of the stereogenic center and active site of the protein.
A number of steps were required to discover an orally bioavailable inhibitor in vivo similar to that seen with the iV-hydroxyureas (2). The compound discovered was improved by structural modification of the naphthyl ring, and further introduction of a fluoro substituent to reduce susceptibility to metabolism. This compound was ZD2138 (12) (IC50 =
0.02 juAf, human whole blood) (155).ZD2138 possesses no redox properties and extensive SAR data and detailed conformational analyses suggest that the (methoxyalkyl)thiazole and tetrahydropyran (THP) series are related (156). ZD2138 shows no inhibition of CO, even up to 20,000 times the levels that inhibit 5-LO in dog or human blood. ZD2138 does not antagonize FLAP.
In phase I studies, ZD2138 was well tolerated up to 1000 mg per volunteer. A single oral 350 mg dose completely inhibited LT synthesis ex vivo in stimulated blood for over 24 hand the half-life in humans was estimated to be 12-16 h (157). Phase II clinical trials demonstrated that in aspirin-sensitive asthmatic pa-
tients, 350 mg p.o. given 4 h before challenge caused bronchodilation and inhibited the fall in FEV1 (158). However, in allergen-challenged asthmatics the same treatment with ZD2138 had no effect on the early or late asthmatic response (159). Further development of ZD2138 was suspended (160). A detailed description of the discovery of ZD2138 can be found in Ref. 161.
Extension of the work in the Zeneca group around this series led to ZD4407 (13), which is
extremely potent (IC50 = 0.02 ¡jM, human whole blood leukotriene inhibition) and is devoid of any autoinduction of liver enzymes that had been observed preclinically for earlier members of this series (162).
The methoxytetrahydropyran moiety has been exploited by other groups. Merck Frosst identified a class of lignans derived from a natural product, Justicidin E, as moderately potent redox inhibitors of 5-LO (163). Abbott also described compounds in this arena (164). These compounds were very weak inhibitors of 5-LO in broken cell preparations, as was although many compounds with potent whole blood activity were obtained. These data imply a different mode of action for this series than direct 5-LO inhibition and are inconsistent with a substrate inhibitor.
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