Abstract
We report herein the design, synthesis, and pharmacological characterization of a library of novel aryl pyrazol-1-yl-propanamides as selective androgen receptor degraders (SARDs) and pan-antagonists that exert broad-scope AR antagonism. Pharmacological evaluation demonstrated that introducing a pyrazole moiety as the B-ring structural element in the common A-ring-linkage-B-ring nonsteroidal antiandrogens' general pharmacophore allowed the development of a new scaffold of small molecules with unique SARD and pan-antagonist activities even compared to our recently published AF-1 binding SARDs such as UT-155 (9) and UT-34 (10). Novel B-ring pyrazoles exhibited potent AR antagonist activities, including promising distribution, metabolism, and pharmacokinetic properties, and broad-spectrum AR antagonist properties, including potent in vivo antitumor activity. 26a was able to induce an 80% tumor growth inhibition of xenografts derived from the enzalutamide-resistant (Enz-R) VCaP cell line. These results represent an advancement toward the development of novel AR antagonists for the treatment of Enz-R prostate cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Androgen Receptor Antagonists / chemistry
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Androgen Receptor Antagonists / metabolism
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Androgen Receptor Antagonists / pharmacology*
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Androgen Receptor Antagonists / therapeutic use
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Animals
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Benzamides
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Design
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Drug Resistance, Neoplasm / drug effects*
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Half-Life
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Humans
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Male
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Mice
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Microsomes, Liver / metabolism
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Nitriles
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Phenylthiohydantoin / analogs & derivatives
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Phenylthiohydantoin / pharmacology
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Phenylthiohydantoin / therapeutic use
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Prostatic Neoplasms / drug therapy
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Pyrazoles / chemistry*
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Pyrazoles / pharmacology
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Pyrazoles / therapeutic use
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Rats
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Rats, Sprague-Dawley
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Receptors, Androgen / chemistry
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Receptors, Androgen / metabolism*
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Androgen Receptor Antagonists
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Antineoplastic Agents
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Benzamides
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Nitriles
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Pyrazoles
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Receptors, Androgen
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Phenylthiohydantoin
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enzalutamide