6-Substituted 3,4-dihydro-naphthalene-2-carboxylic acids: synthesis and structure-activity studies in a novel class of human 5alpha reductase inhibitors.
Novel 3,4-dihydro-naphthalene-2-carboxylic acids were synthesized and evaluated for 5alpha reductase inhibitory activity. This enzyme exists in two isoforms and is a pharmacological target for the treatment of benign prostatic hyperplasia, male pattern baldness and acne. In the present study non-steroidal compounds capable of mimicking the transition state of the steroidal substrates were prepared. The synthetic strategy for the preparation of compounds 1-6 consisted of triflation followed by subsequent Heck-type carboxylation or methoxy carbonylation for 6-phenyl-3,4-dihydronaphthalen-2(1H)-one 1c. A Negishi-type coupling reaction between 6-(trifluoro-methanesulfonyloxy)-3,4-dihydro-naphthalene-2-carboxylic acid methyl ester 7b and various aryl bromides led, after further transformations, to 6-substituted 3,4-dihydro-naphthalene-2-carboxylic acids 7-15. In a similar way the corresponding naphthalene-2-carboxylic acids 16 and 17 were obtained. The DU 145 cell line and prostate homogenates served as enzyme sources for the human type 1 and type 2 isozymes, whereas ventral prostate was employed to evaluate rat isozyme inhibitory potency. The most active inhibitors identified in this study were 6-[4-(N,N-dicyclohexylaminocarbonyl)phenyl]-3,4-dihydro-naphthalene-2-carboxylic acid (3) (IC50 = 0.09 microM, rat type 1), 6-[3-(N,N-dicyclohexylaminocarbonyl)phenyl]-3,4-dihydro-naphthalene-2-carboxylic acid (13) (IC50 = 0.75 microM, human type 2; IC50 = 0.81 microM, human type 1) and 6-[4-(N,N-diisopropylamino-carbonyl)phenyl]naphthalene-2-carboxylic acid (16) (IC50 = 0.2 microM, human type 2). The latter compound was shown to deactivate the enzyme in an uncompetitive manner (Ki = 90 nM; Km, Testosterone = 0.8-1.0 microM) similar to the steroidal inhibitor Epristeride. Select inhibitors (13 and 16) were tested in vivo using testosterone propionate-treated, juvenile, orchiectomized SD-rats. None of the compounds was active at a dose of 25 mg/kg. This result might in part be ascribed to the relatively poor in vitro rat isozyme inhibitory potency.
Baston
Eckhard
E
8.5 Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 15 11 50, D-66041 Saarbrücken, Germany.
Salem
Ola I A
OI
Hartmann
Rolf W
RW
D058891:5-alpha Reductase Inhibitors; D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes; D008297:Male; D009919:Orchiectomy; D011467:Prostate / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D058891:5-alpha Reductase Inhibitors; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D007527:Isoenzymes