Fertility study of the new pyrazolopyrimidinone derivative DA-8159 for erectile dysfunction in rats.
DA-8159 (5-[2-propyloxy-5-(1-methyl-2-pyrrolidinylethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidine-7-one, CAS 268203-93-6) is a new pyrazolopyrimidinone derivative for the treatment of erectile dysfunction. The test agent was administered by gavage at dose levels of 0, 17.5, 70, and 280 mg/kg to Sprague-Dawley male rats from 28 days before mating to the end of the mating period, and to females from 14 days before mating to day 6 of gestation. Effects of the test agent on general findings and reproductive performance of parent animals and on early embryonic development were examined. At 280 mg/kg, salivation and hair loss were observed at a high incidence in males and females, respectively. One female out of 24 died during the treatment period. A decrease in food consumption and a decrease in body weight were observed in both sexes. No treatment-related gross findings and histopathological findings were seen, except that the dead animal exhibited atrophy of the thymus. A decrease of prostate weight and an increase of liver, lung and spleen weights were seen. An increase in the period and irregularity of sexual cycle was observed. A decrease in fertility and pregnancy index was also seen. A decrease in the number of corpora lutea, implantations, and litter size was observed. There were no treatment-related changes in precoital time, mating index, sperm parameters, and serum testosterone concentration. At 17.5 mg/kg and 70 mg/kg, there were no adverse effects on all the parameters examined. Based on these results, DA-8159 induces suppressed body weight, decreased food consumption, irregularity in sexual cycle, reduced fertility, and decreased number of corpora lutea, implantations, and litter size at 280 mg/kg and no observed adverse effect levels (NOAELs) of DA-8159 are considered to be 70 mg/kg for general toxicity and reproductive capability of parent animals and for early embryonic development, respectively.
Chung
Moon Koo
MK
Toxicology Division, Korea Institute of Toxicology, Yuseong, Daejeon, Republic of Korea. mkchung@kitox.re.kr
Kim
Jong Choon
JC
Kim
Won Bae
WB
Kang
Kyung Koo
KK
Han
Sang Seop
SS
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D010064:Embryo Implantation / Q000187:drug effects; D007172:Erectile Dysfunction / Q000188:drug therapy*; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects*; D008098:Litter Size / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D012727:Sex Characteristics; D012726:Sexual Behavior, Animal / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects; D013449:Sulfonamides; D013739:Testosterone / Q000097:blood; D000096926:Benzenesulfonamides
D011743:Pyrimidines; D013449:Sulfonamides; D013739:Testosterone; C419664:udenafil; D000096926:Benzenesulfonamides