title: 2-(4-(Biphenyl-4-ylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (HZ52)--a novel type of 5-lipoxygenase inhibitor with favourable molecular pharmacology and efficacy in vivo.
abstract: OBJECTIVE
  5-Lipoxygenase (5-LO) is the key enzyme in the biosynthesis of pro-inflammatory leukotrienes (LTs) representing a potential target for pharmacological intervention with inflammation and allergic disorders. Although many LT synthesis inhibitors are effective in simple in vitro test systems, they frequently fail in vivo due to lack of efficacy. Here, we attempted to assess the pharmacological potential of the previously identified 5-LO inhibitor 2-(4-(biphenyl-4-ylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (HZ52).
  
  
  METHODS
  We evaluated the efficacy of HZ52 in vivo using carrageenan-induced pleurisy in rats and platelet-activating factor (PAF)-induced lethal shock in mice. We also characterized 5-LO inhibition by HZ52 at the cellular and molecular level in comparison with other types of 5-LO inhibitor, that is, BWA4C, ZM230487 and hyperforin.
  
  
  RESULTS
  HZ52, 1.5 mg·kg⁻¹ i.p., prevented carrageenan-induced pleurisy accompanied by reduced LTB(4) levels and protected mice (10 mg·kg⁻¹, i.p.) against PAF-induced shock. Detailed analysis in cell-based and cell-free assays revealed that inhibition of 5-LO by HZ52 (i) does not depend on radical scavenging properties and is reversible; (ii) is not impaired by an increased peroxide tone or by elevated substrate concentrations; and (iii) is little affected by the cell stimulus or by phospholipids, glycerides, membranes or Ca²⁺.
  
  
  CONCLUSIONS
  HZ52 is a promising new type of 5-LO inhibitor with efficacy in vivo and with a favourable pharmacological profile. It possesses a unique 5-LO inhibitory mechanism different from classical 5-LO inhibitors and seemingly lacks the typical disadvantages of former classes of LT synthesis blockers.
authors.affiliation: Pharmazeutisches Institut, Universität Tuebingen, Tuebingen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Greiner
authors.forename: C
authors.initials: C
authors.lastname: Hörnig
authors.forename: A
authors.initials: A
authors.lastname: Rossi
authors.forename: C
authors.initials: C
authors.lastname: Pergola
authors.forename: H
authors.initials: H
authors.lastname: Zettl
authors.forename: M
authors.initials: M
authors.lastname: Schubert-Zsilavecz
authors.forename: D
authors.initials: D
authors.lastname: Steinhilber
authors.forename: L
authors.initials: L
authors.lastname: Sautebin
authors.forename: O
authors.initials: O
authors.lastname: Werz
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis / Q000378:metabolism*; D002210:Caprylates / Q000494:pharmacology*; D002351:Carrageenan; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009685:Nuclear Envelope / Q000187:drug effects / Q000378:metabolism; D010972:Platelet Activating Factor / Q000009:adverse effects / Q000494:pharmacology; D010998:Pleurisy / Q000139:chemically induced / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012769:Shock / Q000139:chemically induced / Q000378:metabolism
chemical_list: C570783:2-(4-(biphenyl-4-ylamino)-6-chloropyrimidin-2-ylthio)octanoic acid; D000893:Anti-Inflammatory Agents; D002210:Caprylates; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D011743:Pyrimidines; D007975:Leukotriene B4; D002351:Carrageenan; D001094:Arachidonate 5-Lipoxygenase