title: 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.affiliation: Evotec (U.K.) Ltd. , 114 Milton Park, Abingdon OX14 4SA, United Kingdom.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Prime
authors.affiliation: Evotec (U.K.) Ltd. , 114 Milton Park, Abingdon OX14 4SA, United Kingdom.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Brookfield
authors.affiliation: Evotec (U.K.) Ltd. , 114 Milton Park, Abingdon OX14 4SA, United Kingdom.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Courtney
authors.affiliation: Evotec (U.K.) Ltd. , 114 Milton Park, Abingdon OX14 4SA, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Gaines
authors.affiliation: Evotec (U.K.) Ltd. , 114 Milton Park, Abingdon OX14 4SA, United Kingdom.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Marston
authors.affiliation: Evotec (U.K.) Ltd. , 114 Milton Park, Abingdon OX14 4SA, United Kingdom.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ichihara
authors.affiliation: Evotec (U.K.) Ltd. , 114 Milton Park, Abingdon OX14 4SA, United Kingdom.
authors.forename: Marie
authors.initials: M
authors.lastname: Li
authors.affiliation: Evotec (U.K.) Ltd. , 114 Milton Park, Abingdon OX14 4SA, United Kingdom.
authors.forename: Darshan
authors.initials: D
authors.lastname: Vaidya
authors.affiliation: Evotec (U.K.) Ltd. , 114 Milton Park, Abingdon OX14 4SA, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Williams
authors.affiliation: Evotec (U.K.) Ltd. , 114 Milton Park, Abingdon OX14 4SA, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Pedret-Dunn
authors.affiliation: Evotec (U.K.) Ltd. , 114 Milton Park, Abingdon OX14 4SA, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Reed
authors.affiliation: Evotec AG , Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schaertl
authors.affiliation: CHDI Management/CHDI Foundation , 6080 Center Drive, Suite 100, Los Angeles, California 90045, United States.
authors.forename: Leticia
authors.initials: L
authors.lastname: Toledo-Sherman
authors.affiliation: CHDI Management/CHDI Foundation , 6080 Center Drive, Suite 100, Los Angeles, California 90045, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Beconi
authors.affiliation: CHDI Management/CHDI Foundation , 6080 Center Drive, Suite 100, Los Angeles, California 90045, United States.
authors.forename: Douglas
authors.initials: D
authors.lastname: Macdonald
authors.affiliation: CHDI Management/CHDI Foundation , 6080 Center Drive, Suite 100, Los Angeles, California 90045, United States.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Muñoz-Sanjuan
authors.affiliation: CHDI Management/CHDI Foundation , 6080 Center Drive, Suite 100, Los Angeles, California 90045, United States.
authors.forename: Celia
authors.initials: C
authors.lastname: Dominguez
authors.affiliation: CHDI Management/CHDI Foundation , 6080 Center Drive, Suite 100, Los Angeles, California 90045, United States.
authors.forename: John
authors.initials: J
authors.lastname: Wityak
keywords: ADME; Celiac disease; SAR; acrylamides; computer-aided drug design; plasma stability