Preclinical pharmacokinetics and skeletal pharmacology of a selective androgen receptor modulator.

摘要

Osteoporosis poses a significant health threat to the elderly population.; Many lines of evidence point to the fact that androgens play a pivotal role in bone biology. The discovery of nonsteroidal AR agonists with tissue selective pharmacologic effects provides a unique opportunity to more clearly define the role of androgens in skeletal growth and maintenance, as well as explore these new therapeutic entities for the treatment of osteoporosis.; The specific aims of this project were to: evaluate the therapeutic potential of S-4 based on its pharmacokinetic parameters in rats (Chapter 2) and delineate the protective (Chapter 3) and/or proliferative (Chapter 4) effects of SARMs on bone in vivo.; We hypothesized that S-4 would be rapidly and completely absorbed after oral administration and avoid some of the historical drawbacks of testosterone administration due to its nonsteroidal structure. As expected, we observed decreased metabolic clearance and enhanced oral bioavailability compared to testosterone. S-4 demonstrates complete bioavailability, short time to peak plasma concentration, and relatively slow metabolic clearance at doses capable of eliciting maximal pharmacologic effect. These properties favor the continued development of S-4 as an orally bioavailable nonsteroidal SARM.; In order to examine the protective effects of S-4 on bone loss, we evaluated the pharmacologic activity of S-4 in a rat model of accelerated bone loss. Our studies clearly show that OVX-induced changes in whole body BMD, body weight, percent fat mass, L5-L6 BMD, femoral BMD, femoral CT, femoral CC, femoral PC, trabecular density, biomechanical strength, and biological markers of bone resorption and formation are modulated by a nonsteroidal SARM. S-4 fully restored whole body BMD, L5-L6 BMD, femoral BMD, cortical content, and biomechanical strength in ovariectomized animals. Taken together, these data suggest that S-4 could provide a novel pharmacological intervention in the prevention of bone loss in postmenopausal women.; Finally, we assessed the anabolic activity of S-4 in an osteopenic rat model. Whole body BMD was fully restored in animals receiving >0.1 mg/day S-4. Regional analysis of the L5-L6 vertebra and the femur by DEXA showed that S-4 completely restored BMD. pQCT results confirmed anabolic effects on the cortical bone in the femur, but trabecular density in the distal femur was unchanged with drug treatment. The lack of effect in trabecular bone was likely due to the lack of preexisting architecture upon which to rebuild lost bone. Complete restoration of the biomechanical strength in the femur further supports our conclusion that S-4 is anabolic in bone. These data suggest that S-4 is likely to significantly reduce the fracture risk in patients with osteoporosis through direct anabolic action on both muscle and bone. S-4 performed as well or better than DHT in these assays. As S-4 is anabolic in bone, orally bioavailable, tissue-selective, and does not cross-react with other steroid hormone receptors, it offers significant advantages over currently available therapies for osteoporosis. (Abstract shortened by UMI.)