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Synthesis and SAR of novel, potent and orally bioavailable benzimidazole inhibitors of poly(ADP-ribose) polymerase (PARP) with a quaternary methylene-amino substituent.
Bioorg Med Chem Lett. 2008 Jul 15; 18(14):3955-8.BM

Abstract

Poly(ADP-ribose) polymerases (PARPs) play significant roles in various cellular functions including DNA repair and control of RNA transcription. PARP inhibitors have been demonstrated to potentiate the effect of cytotoxic agents or radiation in a number of animal tumor models. Utilizing a benzimidazole carboxamide scaffold in which the amide forms a key intramolecular hydrogen bond for optimal interaction with the enzyme, we have identified a novel series of PARP inhibitors containing a quaternary methylene-amino substituent at the C-2 position of the benzimidazole. Geminal dimethyl analogs at the methylene-amino substituent were typically more potent than mono-methyl derivatives in both intrinsic and cellular assays. Smaller cycloalkanes such as cyclopropyl or cyclobutyl were tolerated at the quaternary carbon while larger rings were detrimental to potency. In vivo efficacy data in a B16F10 murine flank melanoma model in combination with temozolomide (TMZ) are described for two optimized analogs.

Authors+Show Affiliations

Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USA. Gui-Dong.Zhu@abbott.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18586490

Citation

Zhu, Gui-Dong, et al. "Synthesis and SAR of Novel, Potent and Orally Bioavailable Benzimidazole Inhibitors of poly(ADP-ribose) Polymerase (PARP) With a Quaternary Methylene-amino Substituent." Bioorganic & Medicinal Chemistry Letters, vol. 18, no. 14, 2008, pp. 3955-8.
Zhu GD, Gandhi VB, Gong J, et al. Synthesis and SAR of novel, potent and orally bioavailable benzimidazole inhibitors of poly(ADP-ribose) polymerase (PARP) with a quaternary methylene-amino substituent. Bioorg Med Chem Lett. 2008;18(14):3955-8.
Zhu, G. D., Gandhi, V. B., Gong, J., Thomas, S., Luo, Y., Liu, X., Shi, Y., Klinghofer, V., Johnson, E. F., Frost, D., Donawho, C., Jarvis, K., Bouska, J., Marsh, K. C., Rosenberg, S. H., Giranda, V. L., & Penning, T. D. (2008). Synthesis and SAR of novel, potent and orally bioavailable benzimidazole inhibitors of poly(ADP-ribose) polymerase (PARP) with a quaternary methylene-amino substituent. Bioorganic & Medicinal Chemistry Letters, 18(14), 3955-8. https://doi.org/10.1016/j.bmcl.2008.06.023
Zhu GD, et al. Synthesis and SAR of Novel, Potent and Orally Bioavailable Benzimidazole Inhibitors of poly(ADP-ribose) Polymerase (PARP) With a Quaternary Methylene-amino Substituent. Bioorg Med Chem Lett. 2008 Jul 15;18(14):3955-8. PubMed PMID: 18586490.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis and SAR of novel, potent and orally bioavailable benzimidazole inhibitors of poly(ADP-ribose) polymerase (PARP) with a quaternary methylene-amino substituent. AU - Zhu,Gui-Dong, AU - Gandhi,Viraj B, AU - Gong,Jianchun, AU - Thomas,Sheela, AU - Luo,Yan, AU - Liu,Xuesong, AU - Shi,Yan, AU - Klinghofer,Vered, AU - Johnson,Eric F, AU - Frost,David, AU - Donawho,Cherrie, AU - Jarvis,Ken, AU - Bouska,Jennifer, AU - Marsh,Kennan C, AU - Rosenberg,Saul H, AU - Giranda,Vincent L, AU - Penning,Thomas D, Y1 - 2008/06/12/ PY - 2008/05/15/received PY - 2008/06/05/revised PY - 2008/06/05/accepted PY - 2008/7/1/pubmed PY - 2008/11/18/medline PY - 2008/7/1/entrez SP - 3955 EP - 8 JF - Bioorganic & medicinal chemistry letters JO - Bioorg Med Chem Lett VL - 18 IS - 14 N2 - Poly(ADP-ribose) polymerases (PARPs) play significant roles in various cellular functions including DNA repair and control of RNA transcription. PARP inhibitors have been demonstrated to potentiate the effect of cytotoxic agents or radiation in a number of animal tumor models. Utilizing a benzimidazole carboxamide scaffold in which the amide forms a key intramolecular hydrogen bond for optimal interaction with the enzyme, we have identified a novel series of PARP inhibitors containing a quaternary methylene-amino substituent at the C-2 position of the benzimidazole. Geminal dimethyl analogs at the methylene-amino substituent were typically more potent than mono-methyl derivatives in both intrinsic and cellular assays. Smaller cycloalkanes such as cyclopropyl or cyclobutyl were tolerated at the quaternary carbon while larger rings were detrimental to potency. In vivo efficacy data in a B16F10 murine flank melanoma model in combination with temozolomide (TMZ) are described for two optimized analogs. SN - 1464-3405 UR - https://www.unboundmedicine.com/medline/citation/18586490/Synthesis_and_SAR_of_novel_potent_and_orally_bioavailable_benzimidazole_inhibitors_of_poly_ADP_ribose__polymerase__PARP__with_a_quaternary_methylene_amino_substituent_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0960-894X(08)00670-7 DB - PRIME DP - Unbound Medicine ER -