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1.
Bioorg Med Chem ; 27(3): 457-469, 2019 02 01.
Article in English | MEDLINE | ID: mdl-30606676

ABSTRACT

The bromodomain and extra-terminal (BET) family of proteins, consisting of the bromodomains containing protein 2 (BRD2), BRD3, BRD4, and the testis-specific BRDT, are key epigenetic regulators of gene transcription and has emerged as an attractive target for anticancer therapy. Herein, we describe the discovery of a novel potent BET bromodomain inhibitor, using a systematic structure-based approach focused on improving potency, metabolic stability, and permeability. The optimized dimethylisoxazole aryl-benzimidazole inhibitor exhibited high potency towards BRD4 and related BET proteins in biochemical and cell-based assays and inhibited tumor growth in two proof-of-concept preclinical animal models.


Subject(s)
Benzimidazoles/pharmacology , Drug Discovery , Isoxazoles/pharmacology , Multiple Myeloma/drug therapy , Transcription Factors/antagonists & inhibitors , Administration, Oral , Animals , Benzimidazoles/chemistry , Benzimidazoles/metabolism , Biological Availability , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Isoxazoles/administration & dosage , Isoxazoles/chemistry , Isoxazoles/metabolism , Mice , Molecular Structure , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Protein Domains/drug effects , Structure-Activity Relationship , Transcription Factors/metabolism
2.
Bioorg Med Chem Lett ; 20(5): 1585-8, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-20137928

ABSTRACT

A series of N1-heterocyclic pyrimidinediones were extensively evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Inhibitor 1 is active against NNRTI-resistant viruses including RT mutant K103N. The co-crystal structure of inhibitor 1 with HIV-1 RT revealed that H-bonds are formed with K101 and K103. Efforts to improve the suboptimal pharmacokinetic profile of 1 resulted in the discovery of compound 13, which represents the lead compound in this series with improved pharmacokinetics and similar potency as inhibitor 1.


Subject(s)
Anti-HIV Agents/chemistry , HIV Reverse Transcriptase/antagonists & inhibitors , Heterocyclic Compounds/chemistry , Pyrimidinones/chemistry , Reverse Transcriptase Inhibitors/chemistry , Thymine/analogs & derivatives , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Binding Sites , Crystallography, X-Ray , Dogs , HIV Reverse Transcriptase/metabolism , Humans , Hydrogen Bonding , Microsomes/metabolism , Mutant Proteins/antagonists & inhibitors , Mutant Proteins/metabolism , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacokinetics , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacokinetics , Structure-Activity Relationship , Thymine/chemical synthesis , Thymine/chemistry , Thymine/pharmacokinetics
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