Yali He

Nonsteroidal Selective Androgen Receptor Modulators (SARMs): Dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit

Interest in the development and therapeutic potential of nonsteroidal tissue-selective androgen receptor modulators (SARMs) has increased dramatically within the past decade. Rapidly expanding knowledge of nuclear hormone receptor structure and function and successful proof-of-principle clinical trials with SARMs have revived an almost dormant search for improved androgens. This Award Address attempts to chronicle the landmark discoveries (with emphasis on our work), organize the SARM landscape into clinically relevant bins, and provide insight into the clinical prospects for SARMs. 1.1. Origins of Androgen Use. An early (1889) and unusual experiment in androgen therapy was performed by Charles Edouard Brown-Sequard, age 72. He administered a testicular extract to himself and reported that he felt “increased vigor and capacity for work”. Despite retrospective suggestions that any effect was purely placebo, this report resulted in widespread use of testicular extracts throughout Europe and North America for several decades. Attempts to isolate the active components of testicular extract failed until 1935 when testosterone (17 hydroxy-4-andosten-3-one) was isolated from bull testes. Shortly thereafter, its synthesis was reported. In the same year, extracts of urine from males were shown to cause nitrogen retention, an indicator of anabolic metabolism. Testosterone was the first anabolic androgen to be used clinically, but its use is limited by its androgenicity and pharmacokinetic (PK) issues. 1 In the latter half of the 20th century, the chemical scaffold of testosterone was modified extensively, producing many

Selective androgen receptor modulators

Androgens regulate diverse physiological processes involving both reproductive and non-reproductive functions. Most of the signalling effects of androgens are mediated through the androgen receptor (AR), a member of the nuclear receptor superfamily of transcription factors. Binding of specific ligands to the AR initiates signalling by translocation of the receptor from the cytoplasmic compartment to the nucleus, its association with co-activator proteins and control of target gene expression. In this article, we review recent patent publications on selective androgen receptor modulators (SARMs) with differential effects on non-reproductive target tissues. A number of non-steroidal synthetic compounds, notably tricyclic pyridinodihydroquinoline derivatives, show promising anabolic effects without any significant action on the prostate and seminal vesicles. The selective action of these compounds on muscle and bone tissues implies important clinical applications for these androgen analogues in the treatment of elderly men and patients with wasting diseases. Various potential approaches for the rational design of androgen analogues with SARM function are also discussed.The present invention relates to androgen receptor targeting agents (ARTA) which demonstrate androgenic and anabolic activity, which are nonsteroidal ligands for the androgen receptor. The selective androgen receptor modulators (SARM) are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of chronic muscular wasting; e) decreasing the incidence of, halting or causing a regression of prostate cancer; f) oral androgen relacement and/or other clinical therpauetic and/or diagnostic areas.

Recent and emerging anti‐diabetes targets

Diabetes is a disease that affects over 150 million people worldwide for which there are multiple oral and injectable medications. Because of trends in obesity and sedentary lifestyles, diabetes rates in both developed and developing countries are increasing at an alarming rate. Current medications are not adequately effective in maintaining long‐term glycemic control in most patients, even when used in combination, leaving diabetics susceptible to developing life threatening and debilitating complications such as cardiovascular disease, blindness, kidney complications, and amputations. Consequently, there is a critical need for more potent pharmacotherapies with novel mechanisms of action. A panel of 20 emerging diabetes targets is presented, and small molecule modulators for each target will be discussed.

Novel nonsteroidal ligands with high binding affinity and potent functional activity for the androgen receptor.

While nonsteroidal androgen receptor (AR) antagonists have been known for many years, and used in the clinic for the treatment of hormone dependent prostate cancer, very little is known about nonsteroidal AR agonists. We designed and synthesized a series of chiral bicalutamide analogs, which bear electron-withdrawing groups (either a cyano or a nitro group at the 4-position and a trifluoromethyl group at the 3-position) in the aromatic A ring, and different substituents at the para position in the aromatic B ring of the parent molecule. We also synthesized a series of racemic bicalutamide analogs, which have a trifluoromethyl group instead of a methyl group at the R(2) position. We examined AR binding affinities of our compounds in a competitive binding assay with a radiolabeled high affinity AR ligand, 3H-mibolerone, and also measured their abilities to stimulate AR-mediated transcriptional activation in a cotransfection assay. These studies demonstrated that (1) nonsteroidal ligands can be structurally modified from known nonsteroidal antiandrogens to generate ligands capable of activating AR-mediated transcriptional activation. (2) R-isomer analogs exhibit higher AR binding affinity and more potent functional activity than their corresponding S-isomers in all cases. (3) All sulphide analogs show higher AR binding affinity and more potent functional activity than their corresponding sulphone analogs, with the exception of ligand R-8. Those ligands which exhibit high AR binding affinity and potent functional activity for human AR may provide effective clinical uses for male fertility, male contraception, and hormone replacement therapy.

Dissociated non-steroidal glucocorticoids: tuning out untoward effects

The endogenous glucocorticoid (GC), cortisol, is involved in maintaining homeostatic balance in glucose regulation and immune response while allowing stress adaptation. The glucocorticoid receptor (GR) is required to maintain life and is the target of numerous FDA-approved drugs. Synthetic steroidal GCs are useful in a plethora of conditions characterized by excessive inflammatory or immune responses. Unfortunately, the GCs used at present have potentially dose-limiting and debilitating side effects, some of which derive from the glucose regulatory role of GCs. Consequently, there is a great need to find agents which preserve the potent immune effects without the side effects. This manuscript reviews the existing patent literature on these intensely sought non-steroidal agents that dissociate the therapeutic from metabolic effects, or specifically retain certain GR target effects with attenuated untoward effects. The chemical classes and underlying mechanisms (when known) for these non-steroidal GCs are discussed.

Discovery and Preclinical Characterization of Novel Small Molecule TRK and ROS1 Tyrosine Kinase Inhibitors for the Treatment of Cancer and Inflammation

Receptor tyrosine kinases (RTKs), in response to their growth factor ligands, phosphorylate and activate downstream signals important for physiological development and pathological transformation. Increased expression, activating mutations and rearrangement fusions of RTKs lead to cancer, inflammation, pain, neurodegenerative diseases, and other disorders. Activation or over-expression of ALK, ROS1, TRK (A, B, and C), and RET are associated with oncogenic phenotypes of their respective tissues, making them attractive therapeutic targets. Cancer cDNA array studies demonstrated over-expression of TRK-A and ROS1 in a variety of cancers, compared to their respective normal tissue controls. We synthesized a library of small molecules that inhibit the above indicated RTKs with picomolar to nanomolar potency. The lead molecule GTx-186 inhibited RTK-dependent cancer cell and tumor growth. In vitro and in vivo growth of TRK-A-dependent IMR-32 neuroblastoma cells and ROS1-overexpressing NIH3T3 cells were inhibited by GTx-186. GTx-186 also inhibited inflammatory signals mediated by NFκB, AP-1, and TRK-A and potently reduced atopic dermatitis and air-pouch inflammation in mice and rats. Moreover, GTx-186 effectively inhibited ALK phosphorylation and ALK-dependent cancer cell growth. Collectively, the RTK inhibitor GTx-186 has a unique kinase profile with potential to treat cancer, inflammation, and neuropathic pain.

Non-steroidal glucocorticoid receptor antagonists: the race to replace RU-486 for anti-glucocorticoid therapy

The endogenous glucocorticoid, cortisol, elevates blood glucose and suppresses the immune system. Glucocorticoid (GC) levels rapidly increase in response to physiologic and mental stress, thereby allowing stress adaptation. Unfortunately, the GC response can be excessive, especially under stressful conditions for the organism. The resulting hypercortisolemia is associated with a cluster of symptoms called Cushing’s syndrome, a serious and potentially fatal illness involving hyperglycemia, hypertension, osteoporosis, muscle atrophy and fat maldistribution, as well as psychoses and immunosuppresion. Several disease states, such as diabetes and Cushing’s, would benefit from blocking the actions of endogenous cortisol. The only glucocorticoid receptor (GR) antagonist available in the clinic is the steroid mifepristone (RU-486), whose primary potency is antigestagenic, making its utility as a GR antagonist limited. This manuscript reviews the current patent literature on selective non-steroidal GR antagonists.

Nonsteroidal Selective Androgen Receptor Modulators Enhance Female Sexual Motivation

Women experience a decline in estrogen and androgen levels after natural or surgically induced menopause, effects that are associated with a loss of sexual desire and bone mineral density. Studies in our laboratories have shown the beneficial effects of selective androgen receptor modulators (SARMs) in the treatment of osteoporosis and muscle wasting in animal models. A series of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-propionamide analogs was synthesized to evaluate the effects of B-ring substitutions on in vitro and in vivo pharmacologic activity, especially female sexual motivation. The androgen receptor (AR) relative binding affinities ranged from 0.1 to 26.5% (relative to dihydrotestosterone) and demonstrated a range of agonist activity at 100 nM. In vivo pharmacologic activity was first assessed by using male rats. Structural modifications to the B-ring significantly affected the selectivity of the SARMs, demonstrating that single-atom substitutions can dramatically and unexpectedly influence activity in androgenic (i.e., prostate) and anabolic (i.e., muscle) tissues. (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro,4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide (S-23) displayed full agonist activity in androgenic and anabolic tissues; however, the remaining SARMs were more prostate-sparing, selectively maintaining the size of the levator ani muscle in castrated rats. The partner-preference paradigm was used to evaluate the effects of SARMs on female sexual motivation. With the exception of two four-halo substituted analogs, the SARMs increased sexual motivation in ovariectomized rats, with potency and efficacy comparable with testosterone propionate. These results indicate that the AR is important in regulating female libido given the nonaromatizable nature of SARMs and it could be a superior alternative to steroidal testosterone preparations in the treatment of hypoactive sexual desire disorder.

Hydroxysteroid Dehydrogenase (17β -HSD3, 17β-HSD5, and 3α-HSD3) Inhibitors:Extragonadal Regulation of Intracellular Sex Steroid Hormone Levels

Sex hormone signaling regulates the growth, differentiation and development of many tissues. The intracellular concentrations of sex hormones are regulated by several enzymes, including the 17β-hydroxysteroid dehydrogenases (17β-HSDs) and 3α- hydroxysteroid dehydrogenases (3α-HSDs). Most notably, these enzymes are involved in the oxidation and reduction of ketone and β- hydroxyl groups at the C17 position of androgens and estrogens. Fourteen mammalian 17β-HSDs have been identified to date; and are grouped into oxidative enzymes (17β-HSD types 2, 4, 6, 8, 9, 10, 11 and 14) that catalyze the NAD+-dependent inactivation of sex hormones and reductive enzymes (17β-HSD types 1, 3, 5 and 7) that catalyze the formation of more potent steroid receptor ligands. The proliferative effects of androgens and estrogens in target tissues and over-expression of 17β-HSDs in cancer have led to intense drug discovery efforts to identify and develop 17β-HSD inhibitors that can be used for the treatment of breast, prostate and endometrial cancers, neurological disorders, endometriosis, acne, hirsutism and other hormone dependent and independent diseases. Potent and selective inhibitors of intracellular androgen biosynthesis have been reported and, recent proof-of-concept data suggests that these agents have utility in the treatment of androgen-dependent diseases. This review summarizes recent patents and scientific literature regarding steroidal and nonsteroidal 17β-HSD3, 17β-HSD5, and 3α-HSD3 inhibitors and their promise for treatment of androgen-dependent diseases.

Role and pharmacologic significance of cytochrome P-450 2D6 in oxidative metabolism of toremifene and tamoxifen†‡

We investigated the in vitro metabolism and estrogenic and antiestrogenic activity of toremifene (TOR), tamoxifen (TAM) and their metabolites to better understand the potential effects of cytochrome P‐450 2D6 (CYP2D6) status on the activity of these drugs in women with breast cancer. The plasma concentrations of TOR and its N‐desmethyl (NDM) and 4‐hydroxy (4‐OH) metabolites during steady‐state dosing with TOR were also determined. Unlike TOR, TAM and its NDM metabolite were extensively oxidized to 4‐OH TAM and 4‐OH‐NDM TAM by CYP2D6, and the rate of metabolism was affected by CYP2D6 status. 4‐OH‐NDM TOR concentrations were not measurable at steady state in plasma of subjects taking 80 mg of TOR. Molecular modeling provided insight into the lack of 4‐hydroxylation of TOR by CYP2D6. The 4‐OH and 4‐OH‐NDM metabolites of TOR and TAM bound to estrogen receptor (ER) subtypes with fourfold to 30‐fold greater affinity were 35‐ to 187‐fold more efficient at antagonizing ER transactivation and had antiestrogenic potency that was up to 360‐fold greater than their parent drugs. Our findings suggest that variations in CYP2D6 metabolic capacity may cause significant differences in plasma concentrations of active TAM metabolites (i.e., 4‐OH TAM and 4‐OH‐NDM TAM) and contribute to variable pharmacologic activity. Unlike TAM, the clinical benefits in subjects taking TOR to treat metastatic breast cancer would not likely be subject to allelic variation in CYP2D6 status or affected by coadministration of CYP2D6‐inhibiting medications.