apalutamide and Prostatic-Neoplasms

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 (

Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Resistance, Neoplasm; Half-Life; Humans; Male; Mice; Microsomes, Liver; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Androgen; Structure-Activity Relationship; Xenograft Model Antitumor Assays

In our effort to find small-molecule treatments of advanced prostate cancers (PCs), a novel series of indolyl and indolinyl propanamides (series II and III) were discovered as selective androgen receptor degraders (SARDs). Initial studies of androgen receptor (AR) antagonist (1) and agonist (2) propanamides yielded a tertiary aniline (3) with novel SARD activity but poor metabolic stability. Cyclization to II and III produced submicromolar AR antagonism and protein degradation selective to AR and AR splice variant (AR SV). II and III maintained potency against enzalutamide-resistant (Enz-R) mutant ARs and PC cells and were efficacious in Enz-R xenografts, suggesting their potential to treat advanced PCs. Design, synthesis, and biological activity of novel SARDs that could potentially be used for the treatment of a wide spectrum of PCs including castration-resistant, Enz-R, and/or AR SV-dependent advanced PCs that are often untreatable with known hormone therapies are discussed.

Topics: Amides; Androgen Receptor Antagonists; Androgens; Animals; Benzamides; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Resistance, Neoplasm; Humans; Indoles; Male; Mice; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Proteolysis; Rats; Receptors, Androgen; Structure-Activity Relationship; Xenograft Model Antitumor Assays

A structure-activity relationship study was carried out on a series of thiohydantoins and their analogues 14 which led to the discovery of 92 (MDV3100) as the clinical candidate for the treatment of hormone refractory prostate cancer.

Topics: Androgen Receptor Antagonists; Androgens; Animals; Cell Line, Tumor; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Male; Orchiectomy; Prostatic Neoplasms; Receptors, Androgen; Structure-Activity Relationship; Thiohydantoins; Tumor Burden; Xenograft Model Antitumor Assays