title: Discovery of (2E)-3-{2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an orally active histone deacetylase inhibitor with a superior preclinical profile.
abstract: A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC(50)), liver microsomal stability (t(1/2)), cytochrome P450 inhibitory (3A4 IC(50)), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.
authors.affiliation: Chemistry Discovery, S*BIO Pte Ltd., The Capricorn, Singapore Science Park II, Singapore, Singapore. haishan_wang@sbio.com
authors.forename: Haishan
authors.initials: H
authors.lastname: Wang
authors.forename: Niefang
authors.initials: N
authors.lastname: Yu
authors.forename: Dizhong
authors.initials: D
authors.lastname: Chen
authors.forename: Ken Chi Lik
authors.initials: KC
authors.lastname: Lee
authors.forename: Pek Ling
authors.initials: PL
authors.lastname: Lye
authors.forename: Joyce Wei Wei
authors.initials: JW
authors.lastname: Chang
authors.forename: Weiping
authors.initials: W
authors.lastname: Deng
authors.forename: Melvin Chi Yeh
authors.initials: MC
authors.lastname: Ng
authors.forename: Ting
authors.initials: T
authors.lastname: Lu
authors.forename: Mui Ling
authors.initials: ML
authors.lastname: Khoo
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
authors.forename: Kanda
authors.initials: K
authors.lastname: Sangthongpitag
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wu
authors.forename: Changyong
authors.initials: C
authors.lastname: Hu
authors.forename: Kee Chuan
authors.initials: KC
authors.lastname: Goh
authors.forename: Xukun
authors.initials: X
authors.lastname: Wang
authors.forename: Lijuan
authors.initials: L
authors.lastname: Fang
authors.forename: Kay Lin
authors.initials: KL
authors.lastname: Goh
authors.forename: Hwee Hoon
authors.initials: HH
authors.lastname: Khng
authors.forename: Siok Kun
authors.initials: SK
authors.lastname: Goh
authors.forename: Pauline
authors.initials: P
authors.lastname: Yeo
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Zahid
authors.initials: Z
authors.lastname: Bonday
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: Wood
authors.forename: Brian W
authors.initials: BW
authors.lastname: Dymock
authors.forename: Ethirajulu
authors.initials: E
authors.lastname: Kantharaj
authors.forename: Eric T
authors.initials: ET
authors.lastname: Sun
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D005260:Female; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D009368:Neoplasm Transplantation; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; C557525:SB939 compound; D056284:Histone Deacetylase 1