Irreversible 4-Aminopiperidine Transglutaminase 2 Inhibitors for Huntington's Disease.

Abstract

A new series of potent TG2 inhibitors are reported that employ a 4-aminopiperidine core bearing an acrylamide warhead. We establish the structure-activity relationship of this new series and report on the transglutaminase selectivity and in vitro ADME properties of selected compounds. We demonstrate that the compounds do not conjugate glutathione in an in vitro setting and have superior plasma stability over our previous series.

• Authors: Michael E Prime, Frederick A Brookfield, Stephen M Courtney, Simon Gaines, Richard W Marston, Osamu Ichihara, Marie Li, Darshan Vaidya, Helen Williams, Anna Pedret-Dunn, Laura Reed, Sabine Schaertl, Leticia Toledo-Sherman, Maria Beconi, Douglas Macdonald, Ignacio Muñoz-Sanjuan, Celia Dominguez, John Wityak
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 3 Issue 9 Pg. 731-5 (Sep 13 2012) ISSN: 1948-5875 [Print] United States
• PMID: 24900540 (Publication Type: Journal Article)