ABSTRACT
Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway-targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of ARN-509, whereas the same response required 100 mg/kg/d of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer.
Subject(s)
Androgen Antagonists/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , Prostatic Neoplasms/drug therapy , Thiohydantoins/therapeutic use , Androgen Antagonists/pharmacokinetics , Anilides/pharmacokinetics , Anilides/therapeutic use , Animals , Antineoplastic Agents, Hormonal/blood , Antineoplastic Agents, Hormonal/pharmacokinetics , Benzamides , Cell Line, Tumor , Cell Proliferation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Mice , Nitriles/pharmacokinetics , Nitriles/therapeutic use , Phenylthiohydantoin/analogs & derivatives , Phenylthiohydantoin/blood , Phenylthiohydantoin/pharmacokinetics , Phenylthiohydantoin/therapeutic use , Rats , Receptors, Androgen/drug effects , Thiohydantoins/blood , Thiohydantoins/chemical synthesis , Thiohydantoins/pharmacokinetics , Tosyl Compounds/pharmacokinetics , Tosyl Compounds/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
We have identified and synthesized a series of imidazole containing dimerization inhibitors of inducible nitric oxide synthase (iNOS). The necessity of key imidazole and piperonyl functionality was demonstrated and SAR studies led to the identification of compound 35, which showed a dose dependant inhibition in multiple pain models, including tactile allodynia induced by spinal nerve ligation (Chung model).
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Hyperalgesia/drug therapy , Imidazoles/chemistry , Imidazoles/therapeutic use , Nitric Oxide Synthase Type II/antagonists & inhibitors , Pain/drug therapy , Protein Multimerization/drug effects , Animals , Enzyme Inhibitors/pharmacology , Female , Humans , Imidazoles/pharmacology , Nitric Oxide Synthase Type II/metabolism , Rats , Rats, Inbred LewABSTRACT
Optimization of a screening hit from uHTS led to the discovery of TGR5 agonist 32, which was shown to have activity in a rodent model for diabetes.
Subject(s)
Hydroxyquinolines/chemical synthesis , Quinolines/chemistry , Receptors, G-Protein-Coupled/agonists , Thiophenes/chemical synthesis , Animals , Diabetes Mellitus, Type 2/drug therapy , Glucagon-Like Peptide 1/metabolism , Hydroxyquinolines/chemistry , Hydroxyquinolines/therapeutic use , Mice , Quinolines/chemical synthesis , Quinolines/therapeutic use , Receptors, G-Protein-Coupled/metabolism , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/therapeutic useABSTRACT
ANA975, a 5-amino-3-beta -D-ribofuranosyl-3H-thiazolo[4,5-d]pyrimidin-2-one derivative, was synthesized in the search of an oral prodrug of isatoribine, a small molecule toll-like receptor 7 (TLR-7) agonist. Several strategies were studied to enable the kilogram-scale synthesis of ANA975. Three general total syntheses are described. In the phase I clinical study of ANA975 against hepatitis C virus (HCV), conversion to isatoribine in plasma was rapid and effective, delivering levels of isatoribine that have been shown to be clinically relevant.
