ABSTRACT
Oxobenzimidazoles (e.g., 1), a novel series of androgen receptor (AR) antagonists, were discovered through de novo design guided by structure-based drug design. The compounds in this series were reasonably permeable and metabolically stable, but suffered from poor solubility. The incorporation of three dimensional structural features led to improved solubility. In addition, the observation of a 'flipped' binding mode of an oxobenzimidazole analog in an AR ligand binding domain (LBD) model, led to the design and discovery of the novel oxindole series (e.g., 2) that is a potent full antagonist of AR.
Subject(s)
Androgen Receptor Antagonists/chemical synthesis , Antineoplastic Agents/chemical synthesis , Benzimidazoles/chemical synthesis , Indoles/chemical synthesis , Receptors, Androgen/chemistry , Androgen Receptor Antagonists/pharmacology , Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , Cell Line, Tumor , Drug Design , Drug Discovery , Humans , Indoles/pharmacology , Ligands , Male , Models, Molecular , Prostatic Neoplasms , Protein Binding , Protein Structure, Secondary , Protein Structure, Tertiary , Receptors, Androgen/metabolism , Solubility , Structure-Activity RelationshipABSTRACT
High throughput cell-based screening led to the identification of 3-aryloxy lactams as potent androgen receptor (AR) antagonists. Refinement of these leads to improve the ADME profile and remove residual agonism led to the discovery of 12, a potent full antagonist with greater oral bioavailability. Improvements in the ADME profile were realized by designing more ligand-efficient molecules with reduced molecular weights and lower lipophilicities.
Subject(s)
Drug Discovery , Lactams/pharmacology , Prostatic Neoplasms/drug therapy , Receptors, Androgen/chemistry , Dose-Response Relationship, Drug , High-Throughput Screening Assays , Humans , Lactams/chemical synthesis , Lactams/chemistry , Male , Models, Molecular , Molecular Structure , Prostatic Neoplasms/surgery , Receptors, Androgen/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
An aryloxy tetramethylcyclobutane was identified as a novel template for androgen receptor (AR) antagonists via cell-based high-throughput screening. Follow-up to the initial "hit" established 5 as a viable lead. Further optimization to achieve full AR antagonism led to the discovery of 26 and 30, both of which demonstrated excellent in vivo tumor growth inhibition upon oral administration in a castration-resistant prostate cancer (CRPC) animal model.
Subject(s)
Androgen Antagonists/chemical synthesis , Antineoplastic Agents/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Cyclobutanes/chemical synthesis , Pyrazoles/chemical synthesis , Administration, Oral , Androgen Antagonists/pharmacokinetics , Androgen Antagonists/pharmacology , Androgens/chemical synthesis , Androgens/pharmacokinetics , Androgens/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line , Cyclobutanes/pharmacokinetics , Cyclobutanes/pharmacology , Drug Resistance, Neoplasm , High-Throughput Screening Assays , Humans , Ligands , Male , Mice , Mice, Nude , Models, Molecular , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275.
