title: Pharmacological characterization of an imidazolopyrazole as novel selective androgen receptor modulator.
abstract: Selective androgen receptor modulators (SARMs) are androgens with tissue-selective activity. SARMs that have anabolic activity on muscle while having minimal stimulatory activity on prostate are classified as SARM agonists. They can be used to prevent the loss of lean body mass that is associated with cancer, immunodeficiency, renal disease and aging. They may also have anabolic activity on bone; thus, unlike estrogens, they may reverse the loss of bone strength associated with aging or hypogonadism. Our in-house effort on SARM program discovers a nonsteroidal androgen receptor ligand with a unique imidazolopyrazole moiety in its structure. In vitro, this compound is a weak androgen receptor binder and a weak androgen agonist. Despite this, in orchidectomized mature rats it is an effective SARM agonist, with an ED(50) on levator ani muscle of 3.3mg/kg and an ED(50) on ventral prostate of >30mg/kg. It has its maximal effect on muscle at the dose of 10mg/kg. In addition, this compound has mixed agonistic and antagonistic activities on prostate, reducing the weight of that tissue in intact rats by 22% at 10mg/kg. The compound does not have significant effect on gonadotropin levels or testosterone levels in both orchidectomized and intact male rats. It does not have notable progestin, estrogen or glucocorticoid agonistic or antagonistic activity in rats. In a female sexual behavior model, it improves the sexual desire of ovariectomized female rats for sexually mature intact males over nonsexually ovariectomized females. Overall, the imidazolopyrazole is a potent prostate-sparing candidate for development as a SARM agonist with an appropriate pharmacological profile for clinical benefit in muscle-wasting conditions and female sexual function disorders.
authors.affiliation: Janssen Research and Development LLC, Welsh&McKean Roads, Spring House, PA 19477, USA. xzhang5@its.jnj.com
authors.forename: Xuqing
authors.initials: X
authors.lastname: Zhang
authors.forename: George F
authors.initials: GF
authors.lastname: Allan
authors.forename: Pamela
authors.initials: P
authors.lastname: Tannenbaum
authors.forename: Tifanie
authors.initials: T
authors.lastname: Sbriscia
authors.forename: Olivia
authors.initials: O
authors.lastname: Linton
authors.forename: Muh-Tsann
authors.initials: MT
authors.lastname: Lai
authors.forename: Donna
authors.initials: D
authors.lastname: Haynes-Johnson
authors.forename: Sheela
authors.initials: S
authors.lastname: Bhattacharjee
authors.forename: Scott G
authors.initials: SG
authors.lastname: Lundeen
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Sui
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry / Q000494:pharmacology; D000728:Androgens / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D005260:Female; D006728:Hormones / Q000097:blood; D008297:Male; D051379:Mice; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D009919:Orchiectomy; D010052:Ovariectomy; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D011944:Receptors, Androgen / Q000378:metabolism*; D012726:Sexual Behavior, Animal / Q000187:drug effects
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D006728:Hormones; D011720:Pyrazoles; D011944:Receptors, Androgen; C026262:imidazopyrazole