2-Cyano-4-fluoro-1-thiovalylpyrrolidine analogues as potent inhibitors of DPP-IV

Curt D Haffner; Darryl L McDougald; Steven M Reister; Brian D Thompson; Christopher Conlee; Jing Fang; Jonathan Bass; James M Lenhard; Dallas Croom; Melissa B Secosky-Chang; Thaddeus Tomaszek; Donavon McConn; Kevin Wells-Knecht; Paul R Johnson

doi:10.1016/j.bmcl.2005.08.050

2-Cyano-4-fluoro-1-thiovalylpyrrolidine analogues as potent inhibitors of DPP-IV

Bioorg Med Chem Lett. 2005 Dec 1;15(23):5257-61. doi: 10.1016/j.bmcl.2005.08.050. Epub 2005 Sep 15.

Authors

Curt D Haffner¹, Darryl L McDougald, Steven M Reister, Brian D Thompson, Christopher Conlee, Jing Fang, Jonathan Bass, James M Lenhard, Dallas Croom, Melissa B Secosky-Chang, Thaddeus Tomaszek, Donavon McConn, Kevin Wells-Knecht, Paul R Johnson

Affiliation

¹ Department of Medicinal Chemistry, GlaxoSmithKline Research and Development, 5 Moore Drive, Research Triangle Park, NC 27709, USA. curt.d.haffner@gsk.com

PMID: 16168640
DOI: 10.1016/j.bmcl.2005.08.050

Abstract

We report the synthesis and biological activity of a series of 2-cyano-4-fluoro-1-thiovalylpyrrolidine inhibitors of DPP-IV. Within this series, compound 19 provided a potent, selective, and orally active DPP-IV inhibitor which demonstrated a very long duration of action in both rat and dog.

MeSH terms

Administration, Oral
Animals
Dipeptidyl Peptidase 4 / metabolism*
Dogs
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry*
Protease Inhibitors / pharmacology*
Pyrrolidines / chemical synthesis
Pyrrolidines / chemistry*
Pyrrolidines / pharmacology*
Rats
Valine / analogs & derivatives*
Valine / chemical synthesis
Valine / chemistry
Valine / pharmacology

Substances

2-cyano-4-fluoro-1-thiovalylpyrrolidine, methyl-4-methoxyphenyl
Protease Inhibitors
Pyrrolidines
Dipeptidyl Peptidase 4
Valine