title: Discovery of 2-(6-{[(6-fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-carboxamide (CHR-3996), a class I selective orally active histone deacetylase inhibitor.
abstract: A novel series of HDAC inhibitors demonstrating class I subtype selectivity and good oral bioavailability is described. The compounds are potent enzyme inhibitors (IC₅₀ values less than 100 nM), and improved activity in cell proliferation assays was achieved by modulation of polar surface area (PSA) through the introduction of novel linking groups. Employing oral pharmacokinetic studies in mice, comparing drug levels in spleen to plasma, we selected compounds that were tested for efficacy in human tumor xenograft studies based on their potential to distribute into tumor. One compound, 21r (CHR-3996), showed good oral activity in these models, including dose-related activity in a LoVo xenograft. In addition 21r showed good activity in combination with other anticancer agents in in vitro studies. On the basis of these results, 21r was nominated for clinical development.
authors.affiliation: Chroma Therapeutics Ltd., Abingdon, OX14 4RY, UK. david.moffat@chromatherapeutics.com
authors.forename: David
authors.initials: D
authors.lastname: Moffat
authors.forename: Sanjay
authors.initials: S
authors.lastname: Patel
authors.forename: Francesca
authors.initials: F
authors.lastname: Day
authors.forename: Andrew
authors.initials: A
authors.lastname: Belfield
authors.forename: Alastair
authors.initials: A
authors.lastname: Donald
authors.forename: Martin
authors.initials: M
authors.lastname: Rowlands
authors.forename: Judata
authors.initials: J
authors.lastname: Wibawa
authors.forename: Deborah
authors.initials: D
authors.lastname: Brotherton
authors.forename: Lindsay
authors.initials: L
authors.lastname: Stimson
authors.forename: Vanessa
authors.initials: V
authors.lastname: Clark
authors.forename: Jo
authors.initials: J
authors.lastname: Owen
authors.forename: Lindsay
authors.initials: L
authors.lastname: Bawden
authors.forename: Gary
authors.initials: G
authors.lastname: Box
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bone
authors.forename: Paul
authors.initials: P
authors.lastname: Mortenson
authors.forename: Anthea
authors.initials: A
authors.lastname: Hardcastle
authors.forename: Sandra
authors.initials: S
authors.lastname: van Meurs
authors.forename: Suzanne
authors.initials: S
authors.lastname: Eccles
authors.forename: Florence
authors.initials: F
authors.lastname: Raynaud
authors.forename: Wynne
authors.initials: W
authors.lastname: Aherne
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: C555225:2-(6-(((6-fluoroquinolin-2-yl)methyl)amino)bicyclo(3.1.0)hex-3-yl)-N-hydroxypyrimidine-5-carboxamide; D000970:Antineoplastic Agents; D053961:Azabicyclo Compounds; D056572:Histone Deacetylase Inhibitors; D011743:Pyrimidines