GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategies and solutions for achieving desirable potency, rat pharmacokinetics, and physicochemical properties. We highlight the use of conformational bias to deliver potency and optimization of volume of distribution and unbound clearance to enable desirable in vivo mean residence times.

Angewandte ChemieVolume 118, Issue 8 p. 1270-1274 Zuschrift Chemoselective Amide Ligations by Decarboxylative Condensations of N-Alkylhydroxylamines and α-Ketoacids† Jeffrey W. Bode Prof. Dr., bode@chem.ucsb.edu Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA, Fax: (+1) 805-893-4120Search for more papers by this authorRyan M. Fox, Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA, Fax: (+1) 805-893-4120Search for more papers by this authorKyle D. Baucom, Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA, Fax: (+1) 805-893-4120Search for more papers by this author Jeffrey W. Bode Prof. Dr., bode@chem.ucsb.edu Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA, Fax: (+1) 805-893-4120Search for more papers by this authorRyan M. Fox, Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA, Fax: (+1) 805-893-4120Search for more papers by this authorKyle D. Baucom, Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA, Fax: (+1) 805-893-4120Search for more papers by this author First published: 06 February 2006 https://doi.org/10.1002/ange.200503991Citations: 90 † This work was supported by the Donors of the Petroleum Research Fund (administered by the American Chemical Society), the Camille and Henry Dreyfus Foundation (New Faculty Award to J.W.B.), and the University of California. K.D.B. was a 2005 DeWolfe Summer Undergraduate Fellow. We are grateful to Joshua Garretson for preliminary efforts. Read the full textAboutPDF ToolsRequest permissionAdd to favorites ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Abstract Ganz ohne Additiv: Die chemoselektive Ligation zwischen N-Alkylhydroxylaminen und α-Ketosäuren unter Bildung einer Amidbindung erfordert keine Reagentien und hat als einzige Begleitprodukte Wasser und Kohlendioxid. Nicht geschützte Peptidsubstrate werden dabei nicht epimerisiert, was dem Prozess Potenzial als neuartige chemoselektive Ligation zur Synthese von Peptiden und komplexen Materialien verleiht. Citing Literature Supporting Information Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2006/z503991_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume118, Issue8February 13, 2006Pages 1270-1274 This is the German version of Angewandte Chemie. Note for articles published since 1962: Do not cite this version alone. Take me to the International Edition version with citable page numbers, DOI, and citation export. We apologize for the inconvenience. RelatedInformation