Discovery and pharmacological characterization of a novel potent inhibitor of diacylglycerol-sensitive TRPC cation channels

  • Br J Pharmacol. 2015 Jul;172(14):3650-60. doi: 10.1111/bph.13151.
T Maier  1 ,  M Follmann  1 ,  G Hessler  1 ,  H-W Kleemann  1 ,  S Hachtel  1 ,  B Fuchs  2 ,  N Weissmann  2 ,  W Linz  1 ,  T Schmidt  1 ,  M Löhn  1 ,  K Schroeter  1 ,  L Wang  1 ,  H Rütten  1 ,  C Strübing  1
Affiliations
  • 1. Sanofi R&D, Frankfurt am Main, Germany.
  • 2. 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.
PMID: 25847402 DOI: 10.1111/bph.13151
Abstract

Background and purpose: 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.

Experimental approach: 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.

Key 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 and implications: 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.

Products