title: Kidney CLC-K chloride channels inhibitors: structure-based studies and efficacy in hypertension and associated CLC-K polymorphisms.
abstract: OBJECTIVE
  Alterations in the handling of renal salt reabsorption may contribute to interindividual differences in blood pressure regulation and susceptibility to hypertension. CLC-K chloride channels and their accessory subunit barttin play a pivotal role in kidney by controlling chloride and water absorption. Compounds selective for CLC-Ks, such as the benzofuran derivative MT-189, may have a significant therapeutic potential. Here, we assessed the feasibility of using CLC-K blockers in hypertension and aimed at enhancing drug inhibitory affinity.
  
  
  RESULTS
  We demonstrated that acute in-vivo administration of MT-189 to spontaneously hypertensive rats (SHR) caused a reduction of blood pressure and defined the CLC-K/barttin gene expression pattern in kidney of SHR in comparison with normotensive Wistar-Kyoto rats. Based on MT-189, we designed and tested a new series of benzofuran derivatives on CLC-K chloride channels heterologously expressed in HEK293 cells. These studies enabled us to elucidate the causative molecular relationship for obtaining the most potent and selective inhibitor (SRA-36) described so far, with an IC50 of 6.6 ± 1 μmol/l. The biophysical and pharmacological characterization of A447T CLC-Ka and Y315F CLC-Ka, both polymorphisms associated with hypertension, showed that SRA-36 is an efficacious inhibitor of the chloride currents sustained by these polymorphisms. Molecular docking studies allowed hypothesizing an inhibition mechanism for the considered ligands, laying the foundations for the rational design of new and more effective CLC-K inhibitors.
  
  
  CONCLUSIONS
  The SRA-36 molecule represents a new potential therapeutic option for hypertension.
authors.affiliation: aDipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari, Bari bIstituto di Biofisica, CNR, Genova, Italy *Antonella Liantonio and Paola Imbrici contributed equally to the writing of this article.
authors.forename: Antonella
authors.initials: A
authors.lastname: Liantonio
authors.forename: Paola
authors.initials: P
authors.lastname: Imbrici
authors.forename: Giulia Maria
authors.initials: GM
authors.lastname: Camerino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fracchiolla
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Carbonara
authors.forename: Donato
authors.initials: D
authors.lastname: Giannico
authors.forename: Antonella
authors.initials: A
authors.lastname: Gradogna
authors.forename: Giuseppe Felice
authors.initials: GF
authors.lastname: Mangiatordi
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.forename: Domenico
authors.initials: D
authors.lastname: Tricarico
authors.forename: Michael
authors.initials: M
authors.lastname: Pusch
authors.forename: Diana Conte
authors.initials: DC
authors.lastname: Camerino
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D004195:Disease Models, Animal; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects; D062105:Molecular Docking Simulation; D011110:Polymorphism, Genetic; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
chemical_list: C000595238:2-(6-fluoro-3-((4-methoxybenzyl)amino)imidazo(1,2-alpha)pyridin-2-yl)phenol; D001572:Benzofurans; D018118:Chloride Channels; D007093:Imidazoles; D011725:Pyridines