title: Discovery of highly potent, lung-localized epithelial sodium channel inhibitors.
abstract: The design, synthesis and biological evaluation of novel dimeric pyrazinoylguanidines for the treatment of cystic fibrosis (CF) are reported herein. When administered directly to the lung in a guinea pig tracheal potential difference (TPD) model, the dimeric compounds were found to have superior potency, longer duration of action in the lung, and significantly reduced extra-pulmonary exposure in comparison to the corresponding monomeric ENaC blockers, which have been evaluated in the clinic but shown to have dose-limiting kidney toxicity.
authors.affiliation: California Institute for Biomedical Research (Calibr), 11119 North Torrey Pines Road, Suite 100, La Jolla, CA 92037, USA.
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.affiliation: California Institute for Biomedical Research (Calibr), 11119 North Torrey Pines Road, Suite 100, La Jolla, CA 92037, USA.
authors.forename: Gustav
authors.initials: G
authors.lastname: Welzel
authors.affiliation: California Institute for Biomedical Research (Calibr), 11119 North Torrey Pines Road, Suite 100, La Jolla, CA 92037, USA. Electronic address: achatterjee@calibr.org.
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D062686:Epithelial Sodium Channel Blockers / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D006146:Guanidines / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006168:Guinea Pigs; D007668:Kidney / Q000187:drug effects; D008168:Lung / Q000187:drug effects* / Q000378:metabolism*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; D006146:Guanidines
keywords: Dimeric pyrazinoylguanidine; ENaC inhibitors; Guinea pig tracheal potential difference; Non-systemic