Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Editor

Personal info

View

About

Terms

Javascript disabled

Please enable Javascript support in your browser to use this application.

Instructions on how to enable JavaScript on different browsers can be found here: http://www.google.com/support/bin/answer.py?answer=23852.

[edit this page]

Hirsh, A.J. et al.

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, M. Ross Johnson,

Design, synthesis, and structure-activity relationships of novel 2-substituted pyrazinoylguanidine epithelial sodium channel blockers: drugs for cystic fibrosis and chronic bronchitis.

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 IC(50) 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 IC(50) value ever reported for an ENaC blocker.[1]

References

Design, synthesis, and structure-activity relationships of novel 2-substituted pyrazinoylguanidine epithelial sodium channel blockers: drugs for cystic fibrosis and chronic bronchitis. Hirsh, A.J., Molino, B.F., Zhang, J., Astakhova, N., Geiss, W.B., Sargent, B.J., Swenson, B.D., Usyatinsky, A., Wyle, M.J., Boucher, R.C., Smith, R.T., Zamurs, A., Johnson, M.R. J. Med. Chem. (2006) [Pubmed]

Annotations and hyperlinks in this abstract are from individual authors of WikiGenes or automatically generated by the WikiGenes Data Mining Engine. The abstract is from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.About WikiGenes Open Access Licence Privacy Policy Terms of Use apsburg

The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.