Bicalutamide Bicalutamide N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl) sulfonyl-2-hydroxy-2-methylpropanamide Nonsteroidal antiandrogen androgen receptor Dihydrotestosterone testosterone LHRH Casodex AstraZeneca Bicalutamide DHT= Dihydrotestosterone Androgen = Bicalutamide Dihydroepiandrosterone Dihydroepiandrosterone sulfate J. Med. Chem. 1998, 31, Nonseroidal Antiandrogens. Synthesis and Structure-Activity Relationship of 3-Substituted Derivatives of 2-Hydroxypropionanilides. - trifluoromethyl series ( 7, R=CF 3 ) : Partial androgen agonist activity - methyl series ( 7, R=CH 3 ) : pure antagonist * Novel, potent antiandrogens discovery : methyl series 40 (ICI ) Treatment of androgen-responsive benign and malignant disease J. Med. Chem. 1998, 31, Prostate tumor Stimulation Androgen (male sex hormones) Treatment - Orchidectomy ( = castration ) - Estrogen therapy - effective - side effect - cardiovascular complications - painful gynecomastia - impotence - loss of libido Introduction J. Med. Chem. 1998, 31, Introduction Currently available antiandrogens Cyproterone acetate nonsteroidal anilide flutamide * potent progestin, inhibition gonadotrophin secretion * Side effect - loss of libido - gynecomastia - fluid retention - thrombosis * pure antiandrogen * Main side effect - gynecomastia Objective : pure antiandrogen ! - selective for the accessory sex organs - little or no effect on pituitary LH and testosterone secretion J. Med. Chem. 1998, 31, Sulfide 11 sulfone 13 + sulfoxide 12 major minor matabolize Sulfone was the active biological entity. J. Med. Chem. 1998, 31, para substituent : activity * Arylthio analogue * Alkylthio analogue - Ethylthio analogues : activity 53 > > 58, Alkyl group size activity J. Med. Chem. 1998, 31, logP Pyrimidine-0.40 Thiophen ring 1.81 hydrophilic group accessory sex organ selectivity Although potency was retained with a number of heterocyclic rings(64,65,72,73), this was no better than that found in the aryl and alkylthio analogues. J. Med. Chem. 1998, 31, NH OH eclipsed - electron-withdrawing group in the anilide ring - electron properties of R and R Proton-donor ability Crucial factor in receptor interaction - sulfones 49, 53 : dominant conformation in nonpolar solvent - OH group is bound intramolecularly to one of the sulfonyl group oxygen OH group would not be free to participate in receptor interactions Trifluoromethyl group is its enhancement of the proton-donor ability of the tertiary OH group. It is reasonable to attribute the observed agonism to a tighter binding of the trifluoromethyl-substituted compounds to the receptor. J. Med. Chem. 1998, 31, * 17,20,33,40,65,72 : selective antiandrogens * Minor structural changes can affect the selectivity * similar changes in other analogues have no effect * Alkylthio series tended to be nonselective 40 is more potent than flutamide. J. Med. Chem. 1998, 31, summary Effect of introducing substituted methylthio groups onto the tertiary hydroxy-bearing carbon atom of hydroxyflutamide has led to a series of potent antiandrogens, a number of which exhibit selectivity for the accessory sex organs. best selective antiandrogen : 40 (ICI ) Synthesis