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Pharmacokinetics, metabolism, and pharmacologic activities of nonsteroidal selective androgen receptor modulators and their potential application to osteoporosis

Kim, Juhyun
http://rave.ohiolink.edu/etdc/view?acc_num=osu1164223107

Abstract Details

2006, Doctor of Philosophy, Ohio State University, Pharmacy.
The overall objective of this dissertation was to develop a safe, orally active, and affordable drug for the treatment of osteoporosis in men and women. Osteoporotic fractures, particularly vertebral fractures, can result in chronic disabling pain. Although abundant data suggest that androgens are useful for the treatment for osteoporosis, undesirable side effects and pharmacokinetic properties limit their clinical uses. Nonsteroidal selective androgen receptor modulators (SARMs), which we were the first to develop, display higher anabolic activity than androgenic activity in vivo without androgen-related side effects. These nonsteroidal SARMs are more amenable to structural modification and demonstrate high oral bioavailability with long half-life. Due to their favorable characteristics, SARMs are promising as a new treatment of osteoporosis. In the current study, in vitro structure-activity relationship of novel SARMs modified in the aromatic B-ring was analyzed by determining in vitro AR binding affinity and AR-mediated transcriptional activation (Chapter 2). Using two simple criteria (i.e., Ki < 10 nM and lower in vivo clearance), we identified S-22 as a compound with the most potent and tissue-selective in vivo activity that we have observed to date and favorable pharmacokinetic properties (Chapter 3). Halogen-substituted SARMs underwent three major phase I metabolism pathways; 1) hydrolysis of the amide bond, 2) B-ring hydroxylation, 3) A-ring nitro reduction to an aromatic amine. Some of the phase I metabolites underwent phase II metabolisms including sulfation and/or glucuronidation. Moreover, plasma protein binding study suggests that the total clearance of halogen-substituted SARMs was significantly affected by the fraction of drug unbound (Chapter 4). The effects of a SARM (S-22) alone or in combination with SERM (i.e., raloxifene) in bone, muscle, uterus, and body composition were determined. S-22 and raloxifene additively increase bone density and improve microarchitecture of bone with less stimulating effect on uterus than steroidal counterpart. Moreover, S-22 exerted anabolic effect on soleus muscle (Chapter 5). The effects of SARM (S-22) alone or in combination with SERM (raloxifene) on bone cells in vitro were also studied (Chapter 6).
James Dalton (Advisor)
249 p.
Chemistry, Pharmaceutical
Androgen receptor; Selective androgen receptor modulators; Pharmacokinetics; Metabolism; Pharmacology

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Citations

  • Kim, J. (2006). Pharmacokinetics, metabolism, and pharmacologic activities of nonsteroidal selective androgen receptor modulators and their potential application to osteoporosis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1164223107

    APA Style (7th edition)

  • Kim, Juhyun. Pharmacokinetics, metabolism, and pharmacologic activities of nonsteroidal selective androgen receptor modulators and their potential application to osteoporosis. 2006. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1164223107.

    MLA Style (8th edition)

  • Kim, Juhyun. "Pharmacokinetics, metabolism, and pharmacologic activities of nonsteroidal selective androgen receptor modulators and their potential application to osteoporosis." Doctoral dissertation, Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=osu1164223107

    Chicago Manual of Style (17th edition)

osu1164223107
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© 2006, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.