Indazolinones, a new series of redox-active 5-lipoxygenase inhibitors with built-in selectivity and oral activity

J Med Chem. 1991 Mar;34(3):1028-36. doi: 10.1021/jm00107a023.

Abstract

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.

MeSH terms

  • Administration, Oral
  • Animals
  • Chemical Phenomena
  • Chemistry
  • Dinoprostone / biosynthesis
  • Dogs
  • Humans
  • Indazoles / adverse effects
  • Indazoles / chemistry*
  • Indazoles / pharmacology
  • Leukotriene B4 / biosynthesis
  • Lipoxygenase Inhibitors*
  • Male
  • Methemoglobinemia / chemically induced
  • Methylation
  • Molecular Structure
  • Oxidation-Reduction
  • Rats
  • Rats, Inbred Strains
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thromboxane B2 / biosynthesis

Substances

  • Indazoles
  • Lipoxygenase Inhibitors
  • 2-(3-pyridylmethyl)indazolinone
  • Leukotriene B4
  • Thromboxane B2
  • Dinoprostone