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. 2008;6:e010.
doi: 10.1621/nrs.06010. Epub 2008 Nov 26.

Selective Androgen Receptor Modulators in Preclinical and Clinical Development

Free PMC article

Selective Androgen Receptor Modulators in Preclinical and Clinical Development

Ramesh Narayanan et al. Nucl Recept Signal. .
Free PMC article


Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, or end-stage renal disease, osteoporosis, frailty, and hypogonadism. This review summarizes the current standing of research and development of SARMs, crystallography of AR with SARMs, plausible mechanisms for their action and the potential therapeutic indications for this emerging class of drugs.


Figure 1
Figure 1. Mechanism of action.
AR is maintained in an inactive complex by HSP 70 and HSP 90 and corepressors (CoR). Upon ligand binding, the receptor homodimerizes and enters the nucleus. The receptor is basally phosphorylated in the absence of hormone and hormone binding increases the phosphorylation status of the receptor (P). The AR binds to the ARE on the promoter of androgen responsive genes, leading to the recruitment of coactivators (p160s, CBP, TRAP, ARAs) and general transcription factors (GTF), leading to gene transcription.
Figure 2
Figure 2. Discovery of propionamide AR agonists in vitro and in vivo.
The nonsteroidal antiandrogens (1-4) demonstrate therapeutic utility in prostate cancer, and are structurally similar to some nonsteroidal tissue-selective agonists (i.e., SARMs). An early example of which was (5), which was vastly improved by thioether to ether conversion, resulting in the prototypic SARM, S-4 (6). Preclinical characterizations of this molecule catalyzed the development of the SARM field, as discussed herein and in the literature in general.
Figure 3
Figure 3. Quinolinone (pyridone) fused-ring SARMs.
Ligand Pharmaceuticals, Inc. thoroughly explored the structural space surrounding their core quinolinone motif (ring A). SARM activity was achieved using several related templates including: tetrahydropyrido[3,2-g]-quinolin-2(1H)-one (9); anthracenoid (7H-[1,4]oxazino(3,2-g)quinolin-7-ones) (10-11) and phenanthroid (8H-(1,4)oxazino(2,3-f)quinoline-8-ones) (12) oxazino variants; and c) 6-anilino quinolinones (13-15). This latter class produced two clinical candidates in collaboration with TAP Pharmaceuticals. Data shown for (7) and (10) are derived from US Patents US 6,017,924 and 6,462,038, respectively. IC is an abbreviation for intact control. Other abbreviations are as described in the text.
Figure 4
Figure 4. Tetrahydroquinoline (THQ) SARMs.
S-40305 (16) was extensively characterized for its osteoanabolic activity by Hanada et al. Additionally, Kaken scientists patented SARM activity for tetrahydroisoquinoline (THQ) templates 1, 2, and 3. Note that some or all of the data presented for (16-24) was derived from the indicated patents. RBA is an abbreviation for relative binding affinity. Other abbreviations are as described in the text.
Figure 5
Figure 5. Conversion of antagonist to agonist, elimination of mutagenic potential, and various hydantoin replacements.
Bristol-Myers Squibb (BMS) extensively explored antagonist templates and demonstrated the conversion of antagonist templates into agonist templates using a fragmentation approach. This group also explored several [5.5] bicyclic templates as alternatives to their [5.5] bicyclic hydantoin template of BMS-564929 (29). BMS-564929 (29) was characterized as a high potency myoanabolic SARM with high in vivo selectivity as related to the prostate, but a relatively narrow therapeutic index with regard to LH suppression. BMS licensed their SARM program to Pharmacopeia Drug Discovery, including BMS-564929 (29) (now PS178990).
Figure 6
Figure 6. Peer-reviewed SARMs from Johnson & Johnson (J&J) and subsidiaries.
J&J published a wide variety of AR ligand templates, many of which have demonstrated SARM activity (Templates 1-5). These compounds covered a broad range of pharmacological profiles and chemotype diversity. Additionally, J&J patented a wide variety of propionamide bioisosteres (37-41), some of which have not been published. ORX, T, TP, and CaP are abbrevations for orchidectomy, testosterone, testosterone propionate, and prostate cancer, respectively. Other abbreviations are as described in the text.
Figure 7
Figure 7. SARM templates from Merck.
Merck explored several templates, but focused the most effort on the 4-azasteroidal and the butanamide scaffolds, for which they have multiple patents. Merck recently disclosed SARM activity for the first time for (42) at an ACS meeting. (42) was characterized as osteoanabolic with low virilization potential in in vivo rat uterine growth assays (Nantermet et al., 2005). The structures for (43-46) were derived from the indicated patent applications. BFR is an abbreviation for bone formation rate.
Figure 8
Figure 8. SARM templates from GlaxoSmithKline (GSK).
GSK patented an assortment of aniline SARMs (47-54) without specific SARM characterization, but rather just in vitro data. The aniline (55) was characterized in vitro as an AR agonist. Separately, GSK reported in conference abstracts in vitro characterizations of benzoxazepines as AR agonists. GSK has reported their first public disclosure of SARM activity in a conference abstract for GSK2420A (structure not known), and is pursuing GSK971086 (structure not known) as a clinical candidate. Although there is not much public information from GSK, the breadth of their patents and presentations suggests that they have an active SARM program.
Figure 9
Figure 9. SARMs patented by Lilly, Pfizer, and Acadia.
Lilly patented two SARM templates, the N-arylpyrrolidines and tetrahydrocarbazoles, which they characterize as tissue-selective. Unfortunately, their comparisons are to vehicle-treated animals, making it hard to assess the relative activity compared to other templates. Pfizer likewise has patented an aniline series of SARMs, which they characterize as high affinity and tissue-selective full agonists. Acadia too has patented a novel SARM template of [3.2.1] tricyclic anilines, which they characterize as weak anabolic agents that suppress LH at therapeutic doses.
Figure 10
Figure 10. X-ray crystal structures of the AR LBD with DHT and SARMs.
(a) The general protein fold of the AR LBD-DHT complex (PDB code 1i37) superimposed with binding conformations of nonsteroidal SARMs including S-1 from GTx (green, PDB code 2axa), LGD2226 from Ligand Pharmaceuticals (pink, PDB code 2hvc), and ‘10b’ from BMS (purple, PDB code 2ihq) shows how the compounds are accommodated within the agonist form of the AR LBD. Oxygen-red; nitrogen-blue, sulfur-orange; fluorine-cyan. (b) Bound conformation of DHT shows hydrogen bonds between the 3-keto group and R752, as well as the 17α-hydroxyl group with N705 and T877. (c) The A-ring nitro group of S-1 interacts with R752 similar to the 3-keto group of DHT, while the amide NH and hydroxyl groups form hydrogen bonds to L704 and N705, respectively. The B-ring of S-1 orients towards the AF-2 by displacing W741 and the p-fluorine of the B-ring forms a water-mediated hydrogen bond to H874. (d) LGD2226 binds similar to DHT with the ketone on the A-ring hydrogen bonding to R752, but contains an additional hydrogen bond to Q711 through its heterocyclic A-ring. (e) 10b forms hydrogen bonds to R752 and N705 with increased hydrophobic contacts as a result of its bicyclic ring systems.

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