Conformational analysis of 5-lipoxygenase inhibitors: role of the substituents in chiral recognition and on the active conformations of the (methoxyalkyl)thiazole and methoxytetrahydropyran series.
The investigation of the SAR of 5-lipoxygenase (5-LO) inhibition of a series of racemic (methoxyalkyl)thiazoles, exemplified by compound 7 (ZM-211965), has led to other active, racemic derivatives in which the thiazole moiety has been replaced by an ester or an ether. Furthermore, the cyclization of the ethers has given a highly potent, but achiral series, the methoxytetrahydropyrans (methoxyTHP), exemplified by 41 (ZD-2138) presently under clinical evaluation. More recent structural investigations have led to chiral members of this series bearing a 2-methyl substituent in the tetrahydropyran ring. The potential for enantioselectivity in each of the three noncyclic, racemic series led us to synthesize the pure enantiomers ((R)-13c, (S)-13c, (R)-13d, (S)-13d, (R)-15c, (S)-15c, (R)-16b, (S)-16b, and (R)-16c, (S)-16c) and to determine their absolute configuration. The biological activity of each enantiomer was evaluated in intact mouse macrophages and in human whole blood and showed that, of these three series, only the thiazole is enantioselective and that the active configuration is (S) (being between 2 and 3 orders of magnitude more potent than the (R) isomer in mouse macrophages). Conformational analysis using systematic conformational searching, molecular mechanics, and semiempirical methods has been performed on the chiral compounds, and the results have helped to explain the enantioselectivity in the thiazole series and to define the role of the substituents around the quaternary carbon. Simultaneously in the achiral tetrahydropyran (THP) series, the critical role of the methoxy substituent has been examined through the synthesis of the ethyl (24b), ester (22b), methoxymethyl ether (26), hydroxymethyl (25b), aldehyde (27b), ketone (29b), hydroxy (31b), and methyl (23b) analogues and by analysis of their biological and conformational properties. This approach, complemented by the results of a similar study carried out on the Z and E isomers of the chiral ethyl-2-methylTHP derivative (39b and 40b), has also led to the characterization of the active conformation in this series. The whole study has identified new elements to clarify the 3D structural requirements of the 5-LO active site.
Lambert-van der Brempt
C
C
ZENECA Pharma, Centre de Recherches, Reims, France.
Bruneau
P
P
Lamorlette
M A
MA
Foster
S J
SJ
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D016859:Lipoxygenase Inhibitors; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes / Q000737:chemistry*; D011714:Pyrans / Q000737:chemistry*; D015363:Quinolones / Q000737:chemistry*; D012709:Serum Albumin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*
D016859:Lipoxygenase Inhibitors; D009281:Naphthalenes; D011714:Pyrans; D015363:Quinolones; D012709:Serum Albumin; D013844:Thiazoles; C069794:ICI 211965; C075799:ICI D2138; D001094:Arachidonate 5-Lipoxygenase