Structure-activity relationship studies on (4-acylpyrrol-2-yl)alkanoic acids as inhibitors of the cytosolic phospholipase A2: Variation of the alkanoic acid substituent, the acyl chain and the position of the pyrrole nitrogen

https://doi.org/10.1016/S0223-5234(99)80066-XGet rights and content

Summary

(4-Acylpyrrol-2-yl)alkanoic acid derivatives were prepared and evaluated for their ability to inhibit the cytosolic phospholipase A2 of intact bovine platelets. To define the structural requirements for enzyme inhibition, the alkanoic acid group, the acyl residue and the position of the pyrrole nitrogen relative to the pyrrole substituents were varied systematically. Inhibition of cPLA2 was best by compounds containing a free acetic acid or propionic acid group and an acyl chain of 12 or more carbons. The position of the pyrrole nitrogen did not influence the activity significantly. One of the most potent of the cPLA2 inhibitors synthesized was (1,3,5-trimethyl-4-octadecanoylpyrrol-2-yl)acetic acid (IC50: 10 μM).

References (48)

  • VenableME et al.

    J Lipid Res

    (1993)
  • MurakamiM et al.

    J Lipid Mediators Cell Signalling

    (1995)
  • FoxN et al.

    Eur J Pharmacol

    (1996)
  • KramerRM et al.

    J Biol Chem

    (1991)
  • MounierC et al.

    Biochim Biophys Acta

    (1994)
  • ClarkJD et al.

    J Lipid Mediators Cell Signalling

    (1995)
  • RiendeauD et al.

    J Biol Chem

    (1994)
  • MoncadaS et al.

    Ann New York Acad Sci

    (1988)
  • SamuelssonB et al.

    Science

    (1991)
  • MorenoJJ et al.

    Agents Actions

    (1992)
  • HaraS et al.

    J Biochem

    (1989)
  • GronroosJM et al.

    Digestion

    (1992)
  • GreenJA et al.

    Inflammation

    (1991)
  • DillardRD et al.

    J Med Chem

    (1996)
  • TeshirogiI et al.

    J Med Chem

    (1996)
  • TibesU et al.

    Int Arch Allergy Immunol

    (1995)
  • TibesU et al.

    Prostaglandins, Leukotrienes and Essential Fatty Acids

    (1996)
  • ClarkJD et al.
  • GronichJH et al.

    Biochem J

    (1990)
  • WijkanderJ et al.

    Eur J Biochem

    (1991)
  • RoshakA et al.

    J Rheumatol

    (1996)
  • LinLL et al.
  • MounierC et al.

    Eur J Biochem

    (1993)
  • FailiA et al.

    British J Haematol

    (1994)
  • Cited by (15)

    • Pyrrole alkanoic acid derivatives as nuisance inhibitors of microsomal prostaglandin E <inf>2</inf> synthase-1

      2012, European Journal of Medicinal Chemistry
      Citation Excerpt :

      This paper reports the effects of the structural variation of this lead compound on its mPGES-1 inhibitory properties. Quite a few of the pyrroles evaluated for mPGES-1 inhibition have already been published (13–16,18,19,31,34) [35,36,38,39]. For the synthesis of numerous of the dodecanoyl-substituted target compounds (35,43–45,55–67,75) similar synthetic routes were applied as for the preparation of their known corresponding octadecanoyl and octadecyl derivatives, respectively [35,36,38,39].

    • Passerini/tsuji–trost strategy towards pyrrole derivatives

      2017, European Journal of Organic Chemistry
    View all citing articles on Scopus
    View full text