The present invention relates to a novel class of androgen receptor targeting agents (ARTA) which demonstrate androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. The agents define a new subclass of compounds which are selective androgen receptor modulators (SARM) which are useful for mate hormone therapy such as oral testosterone replacement therapy, treating prostate cancer, imaging prostate cancer.
The androgen receptor (xe2x80x9cARxe2x80x9d) is a ligand-activated transcriptional regulatory protein that mediates induction of male sexual development and function through its activity with endogenous androgens. Androgens are generally known as the male sex hormones. The androgenic hormones are steroids which are produced in the body by the testis and the cortex of the adrenal gland, or synthesized in the laboratory. Androgenic steroids play an important role in many physiologic processes, including the development and maintenance of male sexual characteristics such as muscle and bone mass, prostate growth, spermatogenesis, and the male hair pattern (Matsumoto, Endocrinol. Met. Clin. N. Am. 23:857-75 (1994)). The endogenous steroidal androgens include testosterone and dihydrotestosterone (xe2x80x9cDHTxe2x80x9d). Testosterone is the principal steroid secreted by the testes and is the primary circulating androgen found in the plasma of males. Testosterone is converted to DHT by the enzyme 5 alpha-reductase in many peripheral tissues, DHT is thus thought to serve as the intracellular mediator for most androgen actions (Zhou, et al., Molec. Endocrinol. 9:208-18 (1995)). Other steroidal androgens include esters of testosterone, such as the cypionate, propionate, phenylpropionate, cyclopentylpropionate, isocarporate, enanthate, and decanoate esters, and other synthetic androgens such as 7-Methyl-Nortestosterone (xe2x80x9cMENTxe2x80x9d) and its acetate ester (Sundaram et al., xe2x80x9c7 Alpha-Methyl-Nortestosterone(MENT): The Optimal Androgen For Male Contraception,xe2x80x9d Ann. Med., 25:199-205 (1993) (xe2x80x9cSundaramxe2x80x9d)). Because the AR is involved in male sexual development and function, the AR is a likely target for effecting male contraception or other forms of hormone replacement therapy.
Worldwide population growth and social awareness of family planning have stimulated a great deal of research in contraception. Contraception is a difficult subject under any circumstance. It is fraught with cultural and social stigma, religious implications, and, most certainly, significant health concerns. This situation is only exacerbated when the subject focuses on male contraception. Despite the availability of suitable contraceptive to devices, historically, society has looked to women to be responsible for contraceptive decisions and their consequences. Although health concerns over sexually transmitted diseases has made men more aware of the need to develop safe and responsible sexual habits, women still often bear the brunt of contraceptive choice. Women have a number of choices from temporary mechanical devices such as sponges and diaphragms to temporary chemical devices such as spermicides. Women also have at their disposal more permanent options such as physical devices like IUDs and cervical caps as well as more permanent chemical treatments such as birth control pills and subcutaneous implants. However, to date, the only options available for men include the use of condoms and a vasectomy. Condom use, however is not favored by many men because of the reduced sexual sensitivity, the interruption in sexual spontaneity, and the significant possibility of pregnancy caused by breakage or misuse. Vasectomies are also not favored. If more convenient methods of birth control were available to men, particularly long term methods which required no preparative activity immediately prior to a sexual act, such methods could significantly increase the likelihood that men would take more responsibility for contraception.
Administration of the male sex steroids (e.g., testosterone and its derivatives) has shown particular promise in this regard due to the combined gonadotropin-suppressing and androgen-substituting properties of these compounds (Steinberger et al., xe2x80x9cEffect of Chronic Administration of Testosterone Enanthate on Sperm Production and Plasma Testosterone, Follicle Stimulating Hormone, and Luteinizing Hormone Levels: A Preliminary Evaluation of a Possible Male Contraceptive, Fertility and Sterility 28:1320-28 (1977)). Chronic administration of high doses of testosterone completely abolishes sperm production (azoospermia) or reduces it to a very low level (oligospermia). The degree of spermatogenic suppression necessary to produce infertility is not precisely known. However, a recent report by the World Health Organization showed that weekly intramuscular injections of testosterone enanthate result in azoospermia or severe oligospermia (i.e., less than 3 million sperm per ml) and infertility in 98% of men receiving therapy (World Health Organization Task Force on Methods Ar Regulation of Male Fertility, xe2x80x9cContraceptive Efficacy of Testosterone-Induced Azoospermia and Oligospermia in Normal Men,xe2x80x9d Fertilily and Sterility 65:821-29 (1996)).
A variety of testosterone esters have been developed which are more slowly absorbed after intramuscular injection and, thus, result in greater androgenic effect. Testosterone enanthate is the most widely used of these esters. While testosterone enanthate has been valuable in terms of establishing the feasibility of hormonal agents for male contraception, it has several drawbacks, including the need for weekly injections and the presence of supraphysiologic peak levels of testosterone immediately following intramuscular injection (Wu, xe2x80x9cEffects of Testosterone Enanthate in Normal Men: Experience From a Multicenter Contraceptive Efficacy Study,xe2x80x9d Fertility and Sterility 65:626-36 (1996)).
This invention provides a novel class of androgen receptor targeting agents (ARTA). The agents define a new subclass of compounds which are selective androgen receptor modulators (SARM) which are useful for oral testosterone replacement therapy which have an unexpected in-vivo activity for an androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor.
The present invention relates to a selective androgen receptor modulator compound having in-vivo androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor selective androgen receptor modulator compound having the formula (Compound I): 
where X is a O, CH2, NH, Se, PR, or NR;
Z is a hydrogen bond acceptor, NO2, CN, COR, CONHR;
Y is a lipid soluble group, I, CF3, Br, Cl, SnR3;
R is an alkyl group or OH; and
Q is acetamido-, trifluroacetamido-, alkylamines, ether, alkyl, N-sulfonyl, O-sulfonyl, alkylsulfonyl, carbonyl, or a ketone.
The present invention relates to a selective androgen receptor modulator compound having in-vivo androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor selective androgen receptor modulator compound having the formula (Compound II): 
The present invention also relates to a selective androgen receptor modulator compound having in-vivo androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor having the formula (compound III): 
where
X is a O, CH2, NH, Se, PR, or NR;
Z is NO2, CN, COR, or CONHR;
Y is I, CF3, Br, Cl, or SnR3;
R is an alkyl group or OH; and
Q is acetamido or trifluroacetamido.
The present invention also relates to a method of binding a selective androgen receptor modulator compound to a androgen receptor which includes contacting the androgen receptor with the selective androgen receptor modulator compound under conditions effective to bind the selective androgen receptor modulator compound to the androgen receptor.
Another aspect of the present invention relates to a method of suppressing spermatogenesis in a subject which includes contacting an androgen receptor of the subject with a selective androgen receptor modulator compound under conditions effective to suppress spermatogenesis.
The present invention also relates to a method of hormone therapy which comprises administrating to the subject an effective amount of the selective androgen receptor modulator compound. In one embodiment, the selective androgen receptor modulator compound is selective for androgen or testosterone receptor. The present invention also relates to a method of oral administration of the selective androgen receptor modulator compound.
The present invention also relates to a method of hormone therapy which includes contacting an androgen receptor of a patient with a selective androgen receptor modulator compound under conditions effective to bind the selective androgen receptor modulator compound to the androgen receptor and effect a change in an androgen-dependent condition.
The present invention also relates to composition and a pharmaceutical composition which comprises a selective androgen receptor modulator and a suitable carrier or diluent.
Still another aspect of the present relates to a method of producing a selective androgen receptor modulator or a non-steroidal AR agonist compound of the present invention.
The novel selective androgen receptor modulator compounds of the present invention, either alone or as a composition, are useful as a male contraceptive or in the treatment of a variety of hormone-related conditions, such as hypogonadism, sarcopenia, erythropoiesis, and osteoporesis. Further, the selective androgen receptor modulator compounds are useful for oral testosterone replacement therapy.
The selective androgen receptor modulator compounds of the present invention offer a significant advance over steroidal androgen treatment because the selective androgen receptor modulator compounds of the present invention have been shown in-vivo to have an androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. Thus, the selective androgen receptor modulator compounds have an androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor and will not be accompanied by serious side effects, inconvenient modes of administration, or high costs and still have the advantages of oral bioavailability, lack of cross-reactivity with other steroid receptors, and long biological half-lives.