title: Discovery and pharmacological characterization of a novel potent inhibitor of diacylglycerol-sensitive TRPC cation channels.
abstract: OBJECTIVE
  The cation channel transient receptor potential canonical (TRPC) 6 has been associated with several pathologies including focal segmental glomerulosclerosis, pulmonary hypertension and ischaemia reperfusion-induced lung oedema. We set out to discover novel inhibitors of TRPC6 channels and investigate the therapeutic potential of these agents.
  
  
  METHODS
  A library of potential TRPC channel inhibitors was designed and synthesized. Activity of the compounds was assessed by measuring intracellular Ca(2+) levels. The lead compound SAR7334 was further characterized by whole-cell patch-clamp techniques. The effects of SAR7334 on acute hypoxic pulmonary vasoconstriction (HPV) and systemic BP were investigated.
  
  
  RESULTS
  SAR7334 inhibited TRPC6, TRPC3 and TRPC7-mediated Ca(2+) influx into cells with IC50 s of 9.5, 282 and 226 nM, whereas TRPC4 and TRPC5-mediated Ca(2+) entry was not affected. Patch-clamp experiments confirmed that the compound blocked TRPC6 currents with an IC50 of 7.9 nM. Furthermore, SAR7334 suppressed TRPC6-dependent acute HPV in isolated perfused lungs from mice. Pharmacokinetic studies of SAR7334 demonstrated that the compound was suitable for chronic oral administration. In an initial short-term study, SAR7334 did not change mean arterial pressure in spontaneously hypertensive rats (SHR).
  
  
  CONCLUSIONS
  Our results confirm the role of TRPC6 channels in hypoxic pulmonary vasoregulation and indicate that these channels are unlikely to play a major role in BP regulation in SHR. SAR7334 is a novel, highly potent and bioavailable inhibitor of TRPC6 channels that opens new opportunities for the investigation of TRPC channel function in vivo.
authors.affiliation: Sanofi R&D, Frankfurt am Main, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Maier
authors.affiliation: Sanofi R&D, Frankfurt am Main, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Follmann
authors.affiliation: Sanofi R&D, Frankfurt am Main, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Hessler
authors.affiliation: Sanofi R&D, Frankfurt am Main, Germany.
authors.forename: H-W
authors.initials: HW
authors.lastname: Kleemann
authors.affiliation: Sanofi R&D, Frankfurt am Main, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Hachtel
authors.affiliation: Excellencecluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Fuchs
authors.affiliation: Excellencecluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Weissmann
authors.affiliation: Sanofi R&D, Frankfurt am Main, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Linz
authors.affiliation: Sanofi R&D, Frankfurt am Main, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Sanofi R&D, Frankfurt am Main, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Löhn
authors.affiliation: Sanofi R&D, Frankfurt am Main, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Schroeter
authors.affiliation: Sanofi R&D, Frankfurt am Main, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Sanofi R&D, Frankfurt am Main, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Rütten
authors.affiliation: Sanofi R&D, Frankfurt am Main, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Strübing
mesh_terms: D002478:Cells, Cultured; D004075:Diglycerides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004075:Diglycerides; D007189:Indans; C000607554:SAR7334; D050052:TRPC Cation Channels
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