Bicalutamide

Although the traditional steroidal agonists and nonsteroidal antagonists are used for a narrow spectrum of diseases (owing to the factors discussed in Section 8.2.1), these molecules have served as archetypical scaffolds (generalized structural templates) for the development of many other related AR chemotypes with potentially broad therapeutic application. Over 64 chemically distinct putative AR agonist templates have been reported, including 22 templates with demonstrated in vivo tissue-selectivity for anabolic tissues [i.e. selective AR modulators (SARMs)]. 

A potent SARM, S-4 (15), was identified which demonstrated rapid and complete oral absorption at low doses and reasonable elimination half-life (t1/2 = 2.6-5.3 h) in rats, suggesting compounds such as this would be excellent candidates for clinical development [88]. These successes focused our efforts on the diaryl propionanilide class of SARMs of which many have been published [89-92], Recent studies demonstrated that these SARMs improve skeletal (soleus) muscle strength, increase lean body mass (LBM), reduce body fat, prevent bone loss in rats, in addition to promising pharmacologic activity in animal models of benign prostatic hypertrophy and male fertility [92-95], Ostarine is the most advanced SARM clinical candidate and has demonstrated exciting data from its initial proof-of-concept phase II clinical trial. GTx reported in December 2006 the results of this clinical trial which was 

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Bicalutamide may increase the effect of oral anticoagulants. Flutamide enhances the action of leuprolide. Additive antineoplastic effects may occur when leuprolide is administered with megestrol or flutamide. Estrogens decrease the effectiveness of tamoxifen. 

C 2HijF,N202 90357-51-0) see Bicalutamide 4 -cyano-3 -trifIuoromethylmethacrylanilide (CijHijFjNjO 90357-53-2) see Bicalutamide Af-[4-cyano-2-(trifluoromethyl)phenyl]acetamide (C (,H7F,N20 175277-96-0) see Mabuterol /V-(4-cyano-3-trifluoromethylphenyl)-3-(fluorophenyl-sulfanyl)-2-hydroxy-2-methylpropionamide (C,hH,4F4N202S 90356-78-8) see Bicalutamide 2-cyano-3-(3,4,5-trimethoxyphenyl)-2-propenoic acid ethyl ester... 

C4H6O2 79-41-4) see Captopril locetamic acid mcthacryloyl chloride (C4H5CIO 920-46-7) see Bicalutamide methacycline... 

Flutamide is an androgen receptor antagonist that achieves peak concentrations approximately 2 to 4 hours after an oral dose. Flutamide is metabolized extensively, with a terminal half-life of about 8 hours. Bicalutamide achieves peak concentrations approximately 6 hours after the dose, with a terminal half-life of 6 to 10 days. Bicalutamide undergoes stereospecihc metabolism, where the S-enantiomer is cleared more rapidly by the liver than the -enantiomer. Nilutamide achieves peak serum concentrations between 1 to 4 hours after an oral dose and has a terminal half-life of 38 to 60 hours. Nilutamide is metabolized extensively, with less than 2% excreted as unchanged drug by the kidney. Side effects common to these agents are hot flashes, gynecomastia, and decreased libido. Flutamide tends to be associated with more diarrhea and requires three-times-daily administration, whereas bicalutamide is dosed once daily. Nilutamide may cause interstitial pneumonia and is associated with the visual disturbance of delayed adaptation to darkness. 

Bicalutamide 50 mg/day Gynecomastia Hot flushes Gastrointestinal disturbances (diarrhea) Liver function test abnormalities Breast tenderness... 

Boccardo F, Rubagotti A, Barichello M, et al. Bicalutamide monotherapy versus flutamide plus gosrelin in prostate cancer patients Results of an Italian Prostate Cancer Project study. J Clin Oncol 1999 17 2027-2038. 

Bicalutamide -nonsteroidal antiandrogen -endocrine effects -hot flashes -decreased libido -depression -weight gain -constipation... 

Monotherapy with flutamide, bicalutamide, and nilutamide is no longer recommended due to decreased survival as compared with patients treated with LHRH agonist therapy or orchiectomy. Antiandrogens are indicated for advanced prostate cancer only when combined with an LHRH agonist (flutamide and bicalutamide]) or orchiectomy (nilutamide). In combination, antiandrogens can reduce the LHRH agonist-induced flare. 

The adverse effects of antiandrogens are gynecomastia, hot flushes, GI disturbances, liver function test abnormalities, and breast tenderness. GI disturbances consist of diarrhea for flutamide and bicalutamide and nausea or constipation for nilutamide. Flutamide is also associated with methemoglobinemia, whereas nilutamide causes visual disturbances (impaired dark adaptation), alcohol intolerance, and interstitial pneumonitis. 

Prazosin (Minipress) Alfuzosin (Uroxatral) Terazosin (Hytrin) Doxazosin (Cardura) Tamsulosin (Flomax) Finasteride (Proscar) Dutasteride (Avodart) Bicalutamide (Casodex) Flutamide (Eulexin) Leuprolide (Lupron) Nafarelin (Synarel) Megestrol acetate... 

Fluorophenylsulfonyl)-2-hydroxy-2-methyl-propanoic acid (acid side product of bicalutamide)... 

Structural modifications of bicalutamide led to the discovery of the first generation of selective androgen receptor modulators (SARMs). These compounds not only bind to the AR with an affinity in the nanomolar range, but they also show tissue selectivity in animal models [206]. 

In the bicalutamide prostate cancer programme, the adjuvant treatment of patients with advanced prostate carcinoma (T1-T4 NO/NX, MO) with bicalutamide (150 mg, once a day) was evaluated. 4052 patients were randomised to bicalutamide with best standard care (either radiation, prostatectomy or watchful waiting ), whereas 4061 patients received a placebo with best standard care. An initial reduction of prostate cancer recurrence, which was observed in an interim analysis, later was not confirmed [219]. As the survival time in the bicalutamide treatment group was decreased, the study was terminated ahead of time. 

Anastrozole (Arimidex) Bicalutamide (Casodex) Estramustine Phosphate (Estracyt, Emcyt) Exemestane (Aromasin) Fluoxymesterone (Halotestin, Androxy)... 

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