A selective androgen receptor modulator with minimal prostate hypertrophic activity restores lean body mass in aged orchidectomized male rats.
Androgens are required for the maintenance of normal sexual activity in adulthood and for enhancing muscle growth and lean body mass in adolescents and adults. Androgen receptor (AR) ligands with tissue selectivity (selective androgen receptor modulators, or SARMs) have potential for treating muscle wasting, hypogonadism of aging, osteoporosis, female sexual dysfunction, and other indications. JNJ-37654032 is a nonsteroidal AR ligand with mixed agonist and antagonist activity in androgen-responsive cell-based assays. It is an orally active SARM with muscle selectivity in orchidectomized rat models. It stimulated growth of the levator ani muscle with ED(50) 0.8 mg/kg, stimulating maximal growth at a dose of 3mg/kg. In contrast, it stimulated ventral prostate growth to 21% of its full size at 3mg/kg. At the same time, JNJ-37654032 reduced prostate weight in intact rats by 47% at 3mg/kg, while having no inhibitory effect on muscle. Using magnetic resonance imaging to monitor body composition, JNJ-37654032 restored about 20% of the lean body mass lost following orchidectomy in aged rats. JNJ-37654032 reduced follicle-stimulating hormone levels in orchidectomized rats and reduced testis size in intact rats. JNJ-37654032 is a potent prostate-sparing SARM with the potential for clinical benefit in muscle-wasting diseases.
Allan
George
G
Reproductive Therapeutics, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 1000 U.S. Route 202 South, Raritan, NJ, USA. gallan4@prdus.jnj.com
Sbriscia
Tifanie
T
Linton
Olivia
O
Lai
Muh-Tsann
MT
Haynes-Johnson
Donna
D
Bhattacharjee
Sheela
S
Ng
Raymond
R
Sui
Zhihua
Z
Lundeen
Scott
S
D000367:Age Factors; D000726:Androgen Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000818:Animals; D001562:Benzimidazoles / Q000009:adverse effects / Q000494:pharmacology*; D001823:Body Composition / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D008297:Male; D008954:Models, Biological; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000139:chemically induced / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013737:Testis / Q000033:anatomy & histology / Q000187:drug effects; D013851:Thinness / Q000139:chemically induced*
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D001562:Benzimidazoles; C531234:JNJ 37654032