Indazolinones, a new series of redox-active 5-lipoxygenase inhibitors with built-in selectivity and oral activity.
Since the hypothetical mechanisms of hydroperoxydation of arachidonic acid by, respectively, 5-lipoxygenase (5-LPO) and cyclooxygenase (CO) involve a redox cycle, a compound which reduces 5-LPO and CO to their inactive state would give a nonselective inhibitor of both enzymes. Structural modifications of such a compound could be expected to give improved potency and selectivity for 5-LPO and oral activity. Such an approach has led to the discovery of 1,2-dihydroindazol-3-ones which are potent 5-LPO inhibitors with various degrees of selectivity. Structure-activity relationship studies indicated that while N-1,N-2-unsubstituted and N-1-substituted derivatives are orally inactive, N-2-alkyl derivatives are orally active and inhibit both 5-LPO and CO. In contrast, N-2-benzyl derivatives are selective for 5-LPO but possess only weak oral activity. Further structural modifications have identified ICI 207968 [1,2-dihydro-2-(3-pyridylmethyl)-3H-indazol-3-one, 21a] which combines potent oral activity and high selectivity. Methemoglobin (MHb) induction by 21a in dog blood precluded its development for clinical use. Attempts at dissociating 5-LPO inhibitory properties and MHb formation showed that MHb formation in vitro seemed to be related to the redox potential of the compounds whereas 5-LPO inhibition was not. This study led to a series of 4-(N-n-pentylcarbamoyl)indazolinones which maintained in vitro 5-LPO potency but did not induce MHb.
Bruneau
P
P
ICI Pharma, Centre de Recherches, Chemin de Vrilly, Reims, France.
Delvare
C
C
Edwards
M P
MP
McMillan
R M
RM
D000284:Administration, Oral; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D015232:Dinoprostone / Q000096:biosynthesis; D004285:Dogs; D006801:Humans; D007191:Indazoles / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D008297:Male; D008708:Methemoglobinemia / Q000139:chemically induced; D008745:Methylation; D015394:Molecular Structure; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013929:Thromboxane B2 / Q000096:biosynthesis
D007191:Indazoles; D016859:Lipoxygenase Inhibitors; C063962:2-(3-pyridylmethyl)indazolinone; D007975:Leukotriene B4; D013929:Thromboxane B2; D015232:Dinoprostone