This report describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). The characterization of RAD140 in several preclinical models of anabolic androgen action is also described.KEYWORDS Androgen, SARM, cachexia, oxadiazole, Herschberger assay, primate T he androgen receptor (AR) is a member of the steroid hormone nuclear receptor superfamily that includes estrogen, progestin, glucocorticoid and mineralocorticoid receptors. 1 The binding of the prototypical, endogeneously produced androgen testosterone (1) and the important active metabolite dihydrotestosterone (2) to AR initiates a remarkably diverse array of biological activities that can vary according to a subject's sex, age and hormonal status. The activity of AR is critical to normal human sexual development and function, but beyond this signature role, AR activation also has important effects on diverse targets such as bone, liver, muscle and the central nervous system. 2,3 The therapeutic potential of androgen signaling is well-appreciated in the medicinal chemistry community, and for quite some time, chemists have sought compounds that selectively stimulate muscle and bone growth while minimizing the proliferative and/or hypertrophic effects on sex tissues such as the prostate in males and clitoris in females. 4,5 Such compounds have been termed selective androgen receptor modulators or SARMs. In this regard, the prototypical and endogenous androgen, testosterone, is considered to be a logical benchmark comparator. Compound 3 is the GTx SARM S-22 and compound 4 is the BMS SARM 562929, both of which have been reported in the literature as being orally active compounds with selectivity for muscle over prostate relative to testosterone in various preclinical models. 6,7 The possibility of obtaining compounds having tissueselective activities that are different from that of the endogenous benchmark testosterone might derive from the fact that typical AR receptor activation, which is initiated by the binding of a molecule with affinity for the AR to the AR ligand binding domain, is then followed by a rather remarkable, coordinated series of interactions: These may include a change in receptor topology, dissociation of heat shock proteins, receptor dimerization, receptor phosphorylation, rapid-signaling events, translocation to the nucleus (AR), association with many different coregulatory proteins to form a transcriptional complex that results in the activation or suppression of RNA synthesis from AR-modulated genes, and finally receptor degradation. 8 Since each receptor-ligand complex topology is unique to that ligand structure, one can appreciate that the interaction of any particular ligand-receptor complex with coregulatory proteins is likely to be unique to that ligand as well. Furthermore, because the expression level of AR, the constellation and expression level of coregulatory proteins, and the patterns of post-transcriptional regulatory events differ in each type of androgen...
Abaloparatide is a novel, potent and selective activator of parathyroid hormone receptor 1 (PTHR1) under clinical development for the treatment of osteoporosis. We assessed the effect of 6 weeks of abaloparatide on bone mass, microarchitecture, quality and strength in ovariectomized (OVX) rats. After 8 weeks of post-surgical bone depletion (baseline), OVX rats (n = 20–21/group) received daily subcutaneous vehicle (OVX-Veh) or abaloparatide at 5 or 20 µg/kg. Sham-operated control rats (n = 24) received vehicle. Areal bone mineral density (aBMD) of the lumbar spine (L4), total femur and femur diaphysis was measured at baseline and after 6 weeks of treatment. Femur and vertebral bone architecture and mechanical properties were assessed at the end of the treatment phase. At baseline, OVX-Veh rats exhibited significantly lower aBMD relative to Sham controls. Treatment of OVX rats with abaloparatide at 5 or 20 µg/kg/day increased aBMD dose-dependently in the lumbar spine, total femur and femur diaphysis to levels exceeding OVX-Veh or Sham controls. The abaloparatide 5 and 20 µg/kg groups had improved trabecular microarchitecture relative to OVX vehicle, with trabecular BV/TV exceeding OVX-Veh control values by 57 and 78 % (respectively) at the lumbar spine, and by 145 and 270 % at the distal femur. Femur diaphyseal cortical volume and thickness were significantly greater in the abaloparatide 20 µg/kg group relative to OVX vehicle or Sham controls. Bone strength parameters of the femur diaphysis, femur neck and L4 vertebra were significantly improved in the OVX-ABL groups relative to OVX-Veh controls. Bone mass–strength relationships and estimated intrinsic strength properties suggested maintained or improved bone quality with abaloparatide. These data demonstrate skeletal restoration via abaloparatide treatment of osteopenic OVX rats, in association with improved trabecular microarchitecture, cortical geometry and bone strength at sites that have clinical relevance in patients with osteoporosis.
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