title: Design, synthesis, and in vivo SAR of a novel series of pyrazolines as potent selective androgen receptor modulators.
abstract: A novel series of pyrazolines 2 have been designed, synthesized, and evaluated by in vivo screening as tissue-selective androgen receptor modulators (SARMs). Structure-activity relationships (SAR) were investigated at the R1 to R6 positions as well as the core pyrazoline ring and the anilide linker. Overall, strong electron-withdrawing groups at the R1 and R2 positions and a small group at the R5 and R6 position are optimal for AR agonist activity. The (S)-isomer of 7c exhibits more potent AR agonist activity than the corresponding (R)-isomer. (S)-7c exhibited an overall partial androgenic effect but full anabolic effect via oral administration in castrated rats. It demonstrated a noticeable antiandrogenic effect on prostate in intact rats with endogenous testosterone. Thus, (S)-7c is a tissue-selective nonsteroidal androgen receptor modulator with agonist activity on muscle and mixed agonist and antagonist activity on prostate.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, LLC, 665 Stockton Drive, Exton, PA 19341, USA. xzhang@prdus.jnj.com
authors.forename: Xuqing
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Li
authors.forename: George F
authors.initials: GF
authors.lastname: Allan
authors.forename: Tifanie
authors.initials: T
authors.lastname: Sbriscia
authors.forename: Olivia
authors.initials: O
authors.lastname: Linton
authors.forename: Scott G
authors.initials: SG
authors.lastname: Lundeen
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Sui
mesh_terms: D045930:Anabolic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D008297:Male; D015394:Molecular Structure; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000187:drug effects; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D017773:Pelvic Floor; D011467:Prostate / Q000033:anatomy & histology / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000502:physiology
chemical_list: C524108:3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethylphenyl)amide; D045930:Anabolic Agents; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides; D011720:Pyrazoles; D013739:Testosterone