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Article

Design, Synthesis, and Structure−Activity Relationships of Novel 2-Substituted Pyrazinoylguanidine Epithelial Sodium Channel Blockers: Drugs for Cystic Fibrosis and Chronic Bronchitis

Supporting Info

Andrew J. Hirsh,*^‡ Bruce F. Molino,^§ Jianzhong Zhang,^§ Nadezhda Astakhova,^§ William B. Geiss,^§ Bruce J. Sargent,^§ Brian D. Swenson,^§ Alexander Usyatinsky,^§ Michael J. Wyle,^§ Richard C. Boucher, Rick T. Smith,^‡ Andra Zamurs,^‡ and M. Ross Johnson*^‡

Parion Sciences Inc., 2525 Meridian Parkway, Suite 260, Durham, North Carolina 27713, Albany Molecular Research Inc., 21 Corporate Circle, Albany, New York 12212, and Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina at Chapel Hill, Thurston Bowles Building, Chapel Hill, North Carolina 27599

J. Med. Chem., 2006, 49 (14), pp 4098–4115

DOI: 10.1021/jm051134w

Publication Date (Web): June 13, 2006

To whom correspondence should be addressed. Tel: 919-313-1181. Fax: 919-313-1190. E-mails: ajhirsh@Parion.com (A.J.H.). E-mail: mrjohnson@Parion.com (M.R.J).

‡

Parion Sciences Inc.

University of North Carolina at Chapel Hill.

Albany Molecular Research Inc.

Abstract

Amiloride (1), the prototypical epithelial sodium channel (ENaC) blocker, has been administered with limited success as aerosol therapy for improving pulmonary function in patients with the genetic disorder cystic fibrosis. This study was conducted to synthesize and identify more potent, less reversible ENaC blockers, targeted for aerosol therapy and possessing minimal systemic renal activity. A series of novel 2-substituted acylguanidine analogues of amiloride were synthesized and evaluated for potency and reversibility on bronchial ENaC. All compounds tested were more potent and less reversible at blocking sodium-dependent short-circuit current than amiloride. Compounds 30−34 showed the greatest potency on ENaC with IC₅₀ values below 10 nM. A regioselective difference in potency was found (compounds 30, 39, and 40), whereas no stereospecific (compounds 33, 34) difference in potency on ENaC was displayed. Lead compound 32 was 102-fold more potent and 5-fold less reversible than amiloride and displayed the lowest IC₅₀ value ever reported for an ENaC blocker.