1. Bicalutamide 2013.06.17 양혜란

2. Bicalutamide 화학명 N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl) sulfonyl-2-hydroxy-2-methylpropanamide 분류 항암제 약리 Nonsteroidal antiandrogen 으로 androgen receptor 에 결합하여 Dihydrotestosterone 과 testosterone 의 결합을 경쟁적으로 방해 적응증 LHRH 유도체와 병행하여 진행성 전립선암 치료 상품명 Casodex 개발회사 AstraZeneca

3. Bicalutamide 시상하부 뇌하수체 고환 전립선 부신 황체형성 자극 호르몬 황체형성 호르몬 DHT= Dihydrotestosterone Androgen = 남성 생식계의 성장과 발달에 영향을 미치는 호르몬의 총칭

4. Bicalutamide Dihydroepiandrosterone Dihydroepiandrosterone sulfate

5. J. Med. Chem. 1998, 31, 954-959 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 中 40 (ICI 176334) ↓ Treatment of androgen-responsive benign and malignant disease

6. J. Med. Chem. 1998, 31, 954-959 Prostate tumor Stimulation Androgen (male sex hormones) Treatment - Orchidectomy ( = castration ) - Estrogen therapy - effective - side effect - cardiovascular complications - painful gynecomastia - impotence - loss of libido Introduction

7. J. Med. Chem. 1998, 31, 954-959 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 발견 ! - selective for the accessory sex organs - little or no effect on pituitary LH and testosterone secretion

8. J. Med. Chem. 1998, 31, 954-959

9. Sulfide 11 sulfone 13 + sulfoxide 12 major minor matabolize Sulfone was the active biological entity.

10. J. Med. Chem. 1998, 31, 954-959 para substituent : activity ↓ * Arylthio analogue * Alkylthio analogue - Ethylthio analogues : activity ↑ 53 > 55-57 59 > 58, 60-63 - Alkyl group size ↑  activity ↓

11. J. Med. Chem. 1998, 31, 954-959 logP Pyrimidine-0.40 Thiophen ring 1.81 분자 말단에 있는 hydrophilic group 이 accessory sex organ 의 selectivity 에 기여 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.

12. J. Med. Chem. 1998, 31, 954-959 - NH 와 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.

13. J. Med. Chem. 1998, 31, 954-959 * 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.

14. J. Med. Chem. 1998, 31, 954-959 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 176334)

15. Synthesis