title: Parallel medicinal chemistry approaches to selective HDAC1/HDAC2 inhibitor (SHI-1:2) optimization.
abstract: The successful application of both solid and solution phase library synthesis, combined with tight integration into the medicinal chemistry effort, resulted in the efficient optimization of a novel structural series of selective HDAC1/HDAC2 inhibitors by the MRL-Boston Parallel Medicinal Chemistry group. An initial lead from a small parallel library was found to be potent and selective in biochemical assays. Advanced compounds were the culmination of iterative library design and possess excellent biochemical and cellular potency, as well as acceptable PK and efficacy in animal models.
authors.affiliation: Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. sam_kattar@merck.com
authors.forename: Solomon D
authors.initials: SD
authors.lastname: Kattar
authors.forename: Laura M
authors.initials: LM
authors.lastname: Surdi
authors.forename: Anna
authors.initials: A
authors.lastname: Zabierek
authors.forename: Joey L
authors.initials: JL
authors.lastname: Methot
authors.forename: Richard E
authors.initials: RE
authors.lastname: Middleton
authors.forename: Bethany
authors.initials: B
authors.lastname: Hughes
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Szewczak
authors.forename: William K
authors.initials: WK
authors.lastname: Dahlberg
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Kral
authors.forename: Nicole
authors.initials: N
authors.lastname: Ozerova
authors.forename: Judith C
authors.initials: JC
authors.lastname: Fleming
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wang
authors.forename: Paul
authors.initials: P
authors.lastname: Secrist
authors.forename: Andreas
authors.initials: A
authors.lastname: Harsch
authors.forename: Julie E
authors.initials: JE
authors.lastname: Hamill
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cruz
authors.forename: Candia M
authors.initials: CM
authors.lastname: Kenific
authors.forename: Melissa
authors.initials: M
authors.lastname: Chenard
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Miller
authors.forename: Scott C
authors.initials: SC
authors.lastname: Berk
authors.forename: Paul
authors.initials: P
authors.lastname: Tempest
mesh_terms: D000818:Animals; D020650:Combinatorial Chemistry Techniques; D004285:Dogs; D015195:Drug Design; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; C110550:HDAC1 protein, human; C533426:Hdac2 protein, rat; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2