Chapter 1
Analogs and Antagonists of Male Sex Hormones

Robert W. Brueggemeier

The Ohio State University, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Columbus, Ohio, 43210, USA

1. 1 Introduction
2. 2 Historical
3. 3 Endogenous Male Sex Hormones
   1. 3.1 Occurrence and Physiological Roles
   2. 3.2 Biosynthesis
   3. 3.3 Absorption and Distribution
   4. 3.4 Metabolism
      1. 3.4.1 Reductive Metabolism
      2. 3.4.2 Oxidative Metabolism
   5. 3.5 Mechanism of Action
4. 4 Synthetic Androgens
   1. 4.1 Current Drugs on the Market
   2. 4.2 Therapeutic Uses and Bioassays
   3. 4.3 Structure–Activity Relationships for Steroidal Androgens
      1. 4.3.1 Early Modifications
      2. 4.3.2 Methylated Derivatives
      3. 4.3.3 Ester Derivatives
      4. 4.3.4 Halo Derivatives
      5. 4.3.5 Other Androgen Derivatives
      6. 4.3.6 Summary of Structure–Activity Relationships of Steroidal Androgens
   4. 4.4 Nonsteroidal Androgens, Selective Androgen Receptor Modulators (SARMs)
   5. 4.5 Absorption, Distribution, and Metabolism
   6. 4.6 Toxicities
5. 5 Anabolic Agents
   1. 5.1 Current Drugs on the Market
   2. 5.2 Therapeutic Uses and Bioassays
   3. 5.3 Structure–Activity Relationships for Anabolic Agents
      1. 5.3.1 19-Nor Derivatives
      2. 5.3.2 Dehydro Derivatives
      3. 5.3.3 Alkylated Analogs
      4. 5.3.4 Hydroxy and Mercapto Derivatives
      5. 5.3.5 Oxa, Thia, and Aza Derivatives
      6. 5.3.6 Deoxy and Heterocyclic-Fused Analogs
      7. 5.3.7 Esters and Ethers
      8. 5.3.8 Summary of Structure–Activity Relationships
   4. 5.4 Absorption, Distribution, and Metabolism
   5. 5.5 Toxicities
   6. 5.6 Abuse of Anabolic Agents
6. 6 Androgen Antagonists
   1. 6.1 Current Drugs on the Market
   2. 6.2 Antiandrogens
      1. 6.2.1 Therapeutic Uses
      2. 6.2.2 Structure–Activity Relationships for Antiandrogens
      3. 6.2.3 Absorption, Distribution, and Metabolism
      4. 6.2.4 Toxicities
   3. 6.3 Enzyme Inhibitors
      1. 6.3.1 5α-Reductase Inhibitors
      2. 6.3.2 17,20-Lyase Inhibitors
      3. 6.3.3 C19 Steroids as Aromatase Inhibitors
7. 7 Summary
8. Acknowledgments
9. References

Keywords

Androgens

Steroid hormones responsible for the primary and secondary sex characteristics of the male, including the development of the vas deferens, prostate, seminal vesicles, and penis.

Testosterone

The C19 steroid hormone that is the predominant circulating androgen in the bloodstream and is produced mainly by the testis in males.

Dihydrotestosterone

The C19 steroid hormone that is the 5α-reduced metabolite of testosterone. It is produced in certain androgen target tissues and is the most potent endogenous androgen.

Anabolics

Compounds that demonstrate a marked retention of nitrogen through an increase of protein synthesis and a decrease in protein catabolism in the body.

Antiandrogens

Agents that compete with endogenous androgens for the hormone-binding site on the androgen receptor and thus block androgen action.

Selective androgen receptor modulators

Agents that may act as an androgen antagonist or weak agonist in one tissue, but as a strong androgen agonist in another tissue type.

5α-Reductase inhibitors

Compounds that inhibit the conversion of testosterone to its more active metabolite, dihydrotestosterone.

The steroid testosterone is the major circulating sex hormone in males and is the prototype for the androgens, the anabolic agents, and androgen antagonists. Endogenous androgens are biosynthesized from cholesterol; the majority of the circulating androgens are produced in the testes under the stimulation of luteinizing hormone (LH). The reduction of testosterone to dihydrotestosterone is necessary for androgenic actions of testosterone in many androgen target tissues such as the prostate; the oxidation of testosterone by the enzyme aromatase produces estradiol. The androgenic actions of testosterone and dihydrotestosterone are due to their binding to the androgen receptor, followed by nuclear localization, dimerization of the receptor complex, and binding to specific DNA sequences. This binding of the homodimer to the androgen response element leads to gene expression, stimulation, or repression of new mRNA synthesis, and subsequent protein biosynthesis. The synthetic androgens and anabolics were prepared to impart oral activity to the androgen molecule, to separate the androgenic effects of testosterone from its anabolic effects, and to improve on its biological activities. Novel nonsteroidal androgens, termed selective androgen receptor modulators, were developed to impart agonist activity in selective tissues. Drug preparations are used for the treatment of various androgen-deficient diseases and for the therapy of diseases characterized by muscle wasting and protein catabolism. Androgen antagonists include antiandrogens, which block interactions of androgens with the androgen receptor, and inhibitors of androgen biosynthesis and metabolism. Such compounds have therapeutic potential in the treatment of acne, virilization in women, hyperplasia and neoplasia of the prostate, and baldness.

1 Introduction

Androgens are a class of steroids responsible for the primary and secondary sex characteristics of the male. In addition, these steroids possess potent anabolic or growth-promoting properties. The general chemical structure of androgens is based on the androstane C19 steroid, which consists of the fused four-ring steroid nucleus (17 carbons atoms, rings A–D) and the two axial methyl groups (carbons 18 and 19) at the A/B and C/D ring junctions. The hormone testosterone (1) is the predominant circulating androgen and is produced mainly by the testis in males. 5α-Dihydrotestosterone (2) is a 5α-reduced metabolite of testosterone produced in certain target tissues and is the most potent endogenous androgen. Other endogenous androgens are produced by the adrenal gland in both males and females.

These two steroids and other endogenous androgens influence not only the development and maturation of the male genitalia and sex glands, but also affect other tissues such as kidney, liver, and brain. In this chapter, the endogenous androgens, synthetic analogs, various anabolic agents, and the androgen antagonists employed in clinical practice or animal husbandry in the United States and elsewhere will be discussed. Modified androgens that have found use as biochemical or pharmacological tools also are included. More extensive presentations of the topic of androgens, anabolics, and androgen antagonists have appeared in several treatises published over the past four decades [1–11].

2 Historical

The role of the testes in the development and maintenance of the male sex characteristics, and the dramatic physiological effects of male castration, have been recognized since early times. Berthold [12] was the first to publish (in 1849) a report that gonadal transplantation prevented the effects of castration in roosters, suggesting that the testis produced internal secretions exhibiting androgenic effects. However, the elucidation of the molecules of testicular origin responsible for these actions took almost another century. The first report of the isolation of a substance with androgenic activity was made by Butenandt [13, 14], in 1931. The material, isolated in very small quantities from human male urine [15], was named androsterone (3) [16]. A second weakly androgenic steroid hormone was isolated from male urine in 1934; this substance was named dehydroepiandrosterone (4) because of its ready chemical transformation and structural similarity to androsterone [17]. A year later, Laqueur [18, 19] reported the isolation of the testicular androgenic hormone, testosterone (1), which was 10-fold more potent than androsterone in promoting capon comb growth. Shortly after this discovery, the first chemical synthesis of testosterone was reported by Butenandt and Hanisch [20] and confirmed by Ruzicka [21, 22].

For many years, it was believed that testosterone was the active androgenic hormone in man. In 1968, however, research in two laboratories demonstrated that 5α-dihydrotestosterone (DHT, 2), also referred to as stanolone, was the active androgen in certain target tissues such as the prostate and seminal vesicles, and was formed from testosterone by a reductase present in these tissues [23, 24]. Shortly thereafter a soluble receptor protein was isolated and shown to have a greater specificity for DHT and related structures [25, 26]. In general, DHT is thought to be the active androgen in tissues that express 5α-reductase (e.g., the prostate), whereas testosterone appears to directly mediate these effects in muscle and bone.

The anabolic action of the androgens was first documented by Kochakian and Murlin in 1935 [27]. In their experiments, extracts of male urine caused a marked retention of nitrogen when...