title: The development of novel LTA4H modulators to selectively target LTB4generation.
abstract: The pro-inflammatory mediator leukotriene B4(LTB4) is implicated in the pathologies of an array of diseases and thus represents an attractive therapeutic target. The enzyme leukotriene A4hydrolase (LTA4H) catalyses the distal step in LTB4synthesis and hence inhibitors of this enzyme have been actively pursued. Despite potent LTA4H inhibitors entering clinical trials all have failed to show efficacy. We recently identified a secondary anti-inflammatory role for LTA4H in degrading the neutrophil chemoattractant Pro-Gly-Pro (PGP) and rationalized that the failure of conventional LTA4H inhibitors may be that they inadvertently prevented PGP degradation. We demonstrate that these inhibitors do indeed fail to discriminate between the dual activities of LTA4H, and enable PGP accumulation in mice. Accordingly, we have developed novel compounds that potently inhibit LTB4generation whilst leaving PGP degradation unperturbed. These novel compounds could represent a safer and superior class of LTA4H inhibitors for translation into the clinic.
authors.affiliation: Computational Drug Design Consultant, Dulwich, London SE21 8LS, United Kingdom.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Low
authors.affiliation: Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Samia
authors.initials: S
authors.lastname: Akthar
authors.affiliation: Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Dhiren F
authors.initials: DF
authors.lastname: Patel
authors.affiliation: Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Stephan
authors.initials: S
authors.lastname: Löser
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Chi-Tung
authors.initials: CT
authors.lastname: Wong
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.|Birmingham V.A. Medical Center, Birmingham, AL 35294, USA.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Jackson
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: J Edwin
authors.initials: JE
authors.lastname: Blalock
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Hare
authors.affiliation: Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Clare M
authors.initials: CM
authors.lastname: Lloyd
authors.affiliation: Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Snelgrove
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D006868:Hydrolysis; D007249:Inflammation; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D062105:Molecular Docking Simulation; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D015091:beta-Alanine / Q000031:analogs & derivatives
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D011994:Recombinant Proteins; C104311:SC 57461; C113164:prolyl-glycyl-proline; D015091:beta-Alanine; D007975:Leukotriene B4; D011392:Proline; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase