An Orally Active Selective Androgen Receptor Modulator Is Efficacious on Bone, Muscle, and Sex Function with Reduced Impact on Prostate

Abstract

A number of conditions, including osteoporosis, frailty, and sexual dysfunction in both men and women have been improved using androgens. However, androgens are not widely used for these indications because of the side effects associated with these drugs. We describe an androgen receptor (AR) ligand that maintains expected anabolic activities with substantially diminished activity in the prostate. LGD2226 is a nonsteroidal, nonaromatizable, highly selective ligand for the AR, exhibiting virtually no affinity for the other intracellular receptors. We determined that AR bound to LGD2226 exhibits a unique pattern of protein-protein interactions compared with testosterone, fluoxymesterone (an orally available steroidal androgen), and other steroids, suggesting that LGD2226 alters the conformation of the ligand-binding domain. We demonstrated that LGD2226 is fully active in cell-based models of bone and muscle. LGD2226 exhibited anabolic activity on muscle and bone with reduced impact on prostate growth in rodent models. Biomechanical testing of bones from animals treated with LGD2226 showed strong enhancement of bone strength above sham levels. LGD2226 was also efficacious in a sex-behavior model in male rats measuring mounts, intromissions, ejaculations, and copulation efficiency. These results with an orally available, nonaromatizable androgen demonstrate the important role of the AR and androgens in mediating a number of beneficial effects in bone, muscle, and sexual function independent from the conversion of androgens into estrogenic ligands. Taken together, these results suggest that orally active, nonsteroidal selective androgen receptor modulators may be useful therapeutics for enhancing muscle, bone, and sexual function.

Discovery of the Selective Androgen Receptor Modulator MK-0773 Using a Rational Development Strategy Based on Differential Transcriptional Requirements for Androgenic Anabolism Versus Reproductive Physiology

“…3a) were more likely to be tissue-selective. These data support the concept that partial agonism is a reliable, if imperfect, predictor of tissue selectivity, consistent with previous SARM discovery strategies (12)(13)(14)(15)(16)(17)(18)(19)32).…”

“…Raloxifene, for example, is a clinically used selective estrogen receptor modulator that slows bone loss and antagonizes estrogen actions in uterus and breast and reduces the risk of the devel-opment of estrogen receptor-dependent breast cancers (10,11). Preclinical proof of concept for an anabolic SARM with reduced androgenization was established in animal models by several SARMs such as TZP-4238, S-40503, S-1, S-4, LGD2226, LGD2941, JNJ-28330835, and JNJ-37654032 (12)(13)(14)(15)(16)(17)(18)(19). We developed a proof-of-concept SARM, TFM-4AS-1, that increases periosteal bone formation, cortical bone mass, and lean body mass as effectively as DHT but with markedly reduced effects on uterus, prostate, and the pilosebaceous unit (PSU) (20).…”

The Novel Non-steroidal Selective Androgen Receptor Modulator S-101479 Has Additive Effects with Bisphosphonate, Selective Estrogen Receptor Modulator, and Parathyroid Hormone on the Bones of Osteoporotic Female Rats

“…Most SARMs show their selectivity according to the difference between the effects on the prostate (virilizing effect) and that on bone volume or muscle weights (anabolic effect). [13][14][15][16]22,[29][30][31] The reduced virilizing effect that was evaluated by the effect on the prostate is not sufficient to enable treatment for women who require diminished anabolic effects on the uterus. Recently, Merck Research Laboratories demonstrated the effects of bone-selective SARMs in a female animal model 32,33) ; different tissue selectivities are needed to develop postmenopausal osteoporosis drugs.…”

“…[9][10][11][12] Recently, the actions of non-steroidal selective androgen receptor modulators (SARMs) have been investigated in many laboratories. [13][14][15][16][17] Typically, they were observed to be more tissue-selective than anabolic steroids and were orally available in preclinical models. We have focused on bone anabolic SARMs to develop anti-osteoporosis agents without serious virilizing effects.…”

Osteoporosis in Men

“…Problem ve}ine SARM-ova bio je nezadovoljavaju}e razdvajanje njihova u~inka na kost i prostatu (46,47). Ipak, nedavna studija na `ivotinjskom modelu pokazala je da visokoselektivni SARM, LGD2226, inhibira resorpciju spu`vaste kosti a poti~e stvaranje kortikalne kosti, {to rezulira pove}anjem ~vrsto}e kosti (48). Istodobno, u usporedbi s testosteronom, rast prostate je bio zna~ajno manji u `ivotinja koje su dobivale LGD2226 (48).…”