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Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors.
Eur J Med Chem. 2018 Feb 10; 145:389-403.EJ

Abstract

The nuclear protein poly(ADP-ribose) polymerases-1/2 (PARP-1/2) are involved in DNA repair damaged by endogenous or exogenous process. And PARP-1/2 inhibitors have been proved to be clinically efficacious for DNA repair deficient tumors in the past decade. We have developed a series of 4,5,6,7-tetrahydrothienopyridin-2-yl benzimidazole carboxamides as novel and potent PARP-1/2 inhibitors. The best compound resulted from this series is compound 27 which displays excellent PARP-1 and PARP-2 inhibitory activity with IC50 of 18 nM and 42 nM, respectively. Furthermore, it can selectively kill BRCA2 deficient V-C8 cells with a CC50 of 920 nM. In the MDA-MB-436 (BRCA-1 mutant) xenograft model, this compound was well tolerated and showed single-agent activity. Based on the results above, compound 27 has been selected as a lead candidate targeting PARP-1/2 and its preclinical characterization is also underway.

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Authors+Show Affiliations

Chen X
Synthetic Organic & Medicinal Chemistry Laboratory, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
Huan X
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Liu Q
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China; Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Wang Y
Synthetic Organic & Medicinal Chemistry Laboratory, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
He Q
Synthetic Organic & Medicinal Chemistry Laboratory, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Tan C
Synthetic Organic & Medicinal Chemistry Laboratory, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Chen Y
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Ding J
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Xu Y
Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: ycxu@simm.ac.cn.
Miao Z
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: zhmiao@simm.ac.cn.
Yang C
Synthetic Organic & Medicinal Chemistry Laboratory, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: chyang@simm.ac.cn.

MeSH

Administration, OralAnimalsAntineoplastic AgentsBenzimidazolesBody WeightCell LineCell ProliferationCricetulusDose-Response Relationship, DrugDrug DesignDrug Screening Assays, AntitumorHumansMiceModels, MolecularMolecular StructureNeoplasms, ExperimentalPoly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesStructure-Activity RelationshipThermodynamics

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29335205

Citation

Chen, Xuxing, et al. "Design and Synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole Carboxamides as Novel Orally Efficacious Poly(ADP-ribose)polymerase (PARP) Inhibitors." European Journal of Medicinal Chemistry, vol. 145, 2018, pp. 389-403.
Chen X, Huan X, Liu Q, et al. Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors. Eur J Med Chem. 2018;145:389-403.
Chen, X., Huan, X., Liu, Q., Wang, Y., He, Q., Tan, C., Chen, Y., Ding, J., Xu, Y., Miao, Z., & Yang, C. (2018). Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors. European Journal of Medicinal Chemistry, 145, 389-403. https://doi.org/10.1016/j.ejmech.2018.01.018
Chen X, et al. Design and Synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole Carboxamides as Novel Orally Efficacious Poly(ADP-ribose)polymerase (PARP) Inhibitors. Eur J Med Chem. 2018 Feb 10;145:389-403. PubMed PMID: 29335205.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors. AU - Chen,Xuxing, AU - Huan,Xiajuan, AU - Liu,Qiufeng, AU - Wang,Yuqin, AU - He,Qian, AU - Tan,Cun, AU - Chen,Yi, AU - Ding,Jian, AU - Xu,Yechun, AU - Miao,Zehong, AU - Yang,Chunhao, Y1 - 2018/01/08/ PY - 2017/10/11/received PY - 2018/01/05/revised PY - 2018/01/05/accepted PY - 2018/1/18/pubmed PY - 2018/3/3/medline PY - 2018/1/17/entrez KW - 4,5,6,7-Tetrahydrothienopyridine KW - Benzimidazole KW - Co-crystal structure KW - Isothermal Titration Calorimetry KW - PARP1/2 inhibitor SP - 389 EP - 403 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 145 N2 - The nuclear protein poly(ADP-ribose) polymerases-1/2 (PARP-1/2) are involved in DNA repair damaged by endogenous or exogenous process. And PARP-1/2 inhibitors have been proved to be clinically efficacious for DNA repair deficient tumors in the past decade. We have developed a series of 4,5,6,7-tetrahydrothienopyridin-2-yl benzimidazole carboxamides as novel and potent PARP-1/2 inhibitors. The best compound resulted from this series is compound 27 which displays excellent PARP-1 and PARP-2 inhibitory activity with IC50 of 18 nM and 42 nM, respectively. Furthermore, it can selectively kill BRCA2 deficient V-C8 cells with a CC50 of 920 nM. In the MDA-MB-436 (BRCA-1 mutant) xenograft model, this compound was well tolerated and showed single-agent activity. Based on the results above, compound 27 has been selected as a lead candidate targeting PARP-1/2 and its preclinical characterization is also underway. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/29335205/Design_and_synthesis_of_2__4567_tetrahydrothienopyridin_2_yl__benzoimidazole_carboxamides_as_novel_orally_efficacious_Poly_ADP_ribose_polymerase__PARP__inhibitors_ DB - PRIME DP - Unbound Medicine ER -
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