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.
Keywords: Dimeric pyrazinoylguanidine; ENaC inhibitors; Guinea pig tracheal potential difference; Non-systemic.
Copyright © 2015 Elsevier Ltd. All rights reserved.