Androgen Receptor Antagonists (Antiandrogens) Structure-Activity Relationships

Abstract

Prostate cancer, acne, seborrhea, hirsutism, and androgenic alopecia are well recognized to depend upon an excess or increased sensitivity to androgens or to be at least sensitive to androgens. It thus seems logical to use antiandrogens as therapeutic agents to prevent androgens from binding to the androgen receptor. The two predominant naturally occurring androgens are testosterone (T) and dihydrotestosterone (DHT). DHT is the more potent androgen in vivo and in vitro. All androgen-responsive genes are activated by androgen receptor (AR) bound to either T or DHT and it is believed that AR is more transcriptionally active when bound to DHT than T. The two classes of antiandrogens, presently available, are the steroidal derivatives, all of which possess mixed agonistic and antagonistic activities, and the pure non-steroidal antiandrogens of the class of flutamide and its derivatives. The intrinsic androgenic, estrogenic and glucocorticoid activities of steroidal derivatives have limited their use in the treatment of prostate cancer. The non-steroidal flutamide and its derivatives display pure antiandrogenic activity, without exerting agonistic or any other hormonal activity. Flutamide (89) and its derivatives, Casodex (108) and Anandron (114), are highly effective in the treatment of prostate cancer. The combination of flutamide and Anandron with castration has shown prolongation of life in prostate cancer. Furthermore, combined androgen blockade in association with radical prostatectomy or radiotherapy are very effective in the treatment of localized prostate cancer. Such an approach certainly raises the hope of a further improvement in prostate cancer therapy. However, all antiandrogens, developed so-far display moderate affinity for the androgen receptor, and thus moderate efficacy in vitro and in vivo. There is thus a need for next-generation antiandrogens, which could display an equal or even higher affinity for AR compared to the natural androgens, and at the same time maintain its pure antiandrogenic activity, and thus providing improved androgen blockade using possibly antiandrogens alone.

Interaction of organophosphate pesticides and related compounds with the androgen receptor.

“…Previous authors suggested that electron-withdrawal properties of the R3 phenyl substituent enhancing the H-bond acceptor capability at the R2 position are important for antagonism (Singh et al 2000;Teutsch et al 1994;Tucker et al 1988). In contrast, the authors of a recent AR homology study counter that the steric/hydrophobic interaction aspects of this substituent are more important components for binding (Marhefka et al 2001), a view more consistent with the present findings.…”

“…Quantitative structure-activity relationship (QSAR) models and qualitative SAR approaches have had some success in identifying and depicting structural features that contribute to the ability of a chemical to interact with steroid hormones, for both the estrogen receptor (ER) (Anstead et al 1997;Fang et al 2001;McKinney and Waller 1994;Tong et al 1997aTong et al , 1997bTong et al , 1998Waller et al 1996b;Wiese and Brooks 1994) and the AR (Loughney and Schwender 1992;Mekenyan et al 1997;Singh et al 2000;Tucker et al 1988;Waller et al 1996a). In the case of environmentally occurring chemicals, studies have revealed a common pattern of steric and electronic features involved in molecular recognition and receptor binding affinity, in spite of the molecular diversity of such data sets.…”

“…Also pertinent to discerning the structural requirements of AR activity are the results of studies aimed at optimizing antiandrogenic function for the design of pharmaceuticals (Singh et al 2000;Teutsch et al 1994;Tucker et al 1988). The essential rules for antiandrogenic function extracted from these studies are a) an electron-deficient aromatic ring with a strong hydrogen bond (H bond) acceptor (e.g., a nitro or cyano); and b) an aryl-amide linkage to a carbon hosting a strong H-bond donor group at the opposite terminus of the ligand (see, e.g., the essential structural moiety depicted in Figure 2).…”

Indole‐3‐carbinol induces a G1 cell cycle arrest and inhibits prostate‐specific antigen production in human LNCaP prostate carcinoma cells

“…35,41 When they are cultured in medium supplemented with 10% FBS, there are enough steroids and other proliferative factors to support the near-maximal proliferation of these cells in the absence of added exogenous androgens. Under these culture conditions, treatment with flutamide, an androgen antagonist that is used as a therapeutic agent for prostate carcinoma, 43 inhibits the growth of LNCaP cells. In treated cells, flutamide is converted into its more active 2-hydroxylflutamide metabolite.…”

Definitive radiotherapy with adjuvant long-term antiandrogen treatment for locally advanced prostate cancer: health-related quality of life and hormonal changes

“…34,35 Theoretically, the receptor blockade from AAs could therefore be insufficient to affect HRQoL domains such as libido and vitality as these domains are considered to be at least partially androgen dependent. Better HRQoL in patients with particularly high sex hormone concentrations might therefore have been expected.…”