title: SAR Development of Lysine-Based Irreversible Inhibitors of Transglutaminase 2 for Huntington's Disease.
abstract: We report a series of irreversible transglutaminase 2 inhibitors starting from a known lysine dipeptide bearing an acrylamide warhead. We established new SARs resulting in compounds demonstrating improved potency and better physical and calculated properties. Transglutaminase selectivity profiling and in vitro ADME properties of selected compounds are also reported.
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
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: Sayeh
authors.initials: S
authors.lastname: Erfan
authors.affiliation: Evotec (U.K.) Ltd. , 114 Milton Park, Abingdon, OX14 4SA, United Kingdom.
authors.forename: Siw
authors.initials: S
authors.lastname: Johnsen
authors.affiliation: Evotec (U.K.) Ltd. , 114 Milton Park, Abingdon, OX14 4SA, United Kingdom.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Johnson
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: Richard W
authors.initials: RW
authors.lastname: Marston
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 (U.K.) Ltd. , 114 Milton Park, Abingdon, OX14 4SA, United Kingdom.
authors.forename: Darshan
authors.initials: D
authors.lastname: Vaidya
authors.affiliation: Evotec AG , Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schaertl
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: 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
keywords: acrylamides; celiac disease; in vitro ADME; plasma stability; polar surface area