Abstract
We have developed a series of phenylpyrrolidine- and phenylpiperidine-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase (PARP) inhibitors with excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (22b, A-966492). Compound 22b displayed excellent potency against the PARP-1 enzyme with a K(i) of 1 nM and an EC(50) of 1 nM in a whole cell assay. In addition, 22b is orally bioavailable across multiple species, crosses the blood-brain barrier, and appears to distribute into tumor tissue. It also demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide and in an MX-1 breast cancer xenograft model both as a single agent and in combination with carboplatin.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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BRCA1 Protein / deficiency
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / pharmacology
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Benzimidazoles / therapeutic use
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Biological Availability
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Blood-Brain Barrier / metabolism
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Carboplatin / administration & dosage
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Cell Line, Tumor
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Crystallography, X-Ray
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Dacarbazine / administration & dosage
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Dacarbazine / analogs & derivatives
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Drug Screening Assays, Antitumor
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Female
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Melanoma, Experimental / drug therapy
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Mice
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Mice, Inbred C57BL
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Mice, SCID
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Models, Molecular
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Neoplasm Transplantation
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Poly(ADP-ribose) Polymerase Inhibitors*
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Stereoisomerism
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Structure-Activity Relationship
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Temozolomide
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Transplantation, Heterologous
Substances
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2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide
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Antineoplastic Agents
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BRCA1 Protein
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Benzimidazoles
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Poly(ADP-ribose) Polymerase Inhibitors
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Dacarbazine
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Carboplatin
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Temozolomide