title: Fertility study of the new pyrazolopyrimidinone derivative DA-8159 for erectile dysfunction in rats.
abstract: 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.
authors.affiliation: Toxicology Division, Korea Institute of Toxicology, Yuseong, Daejeon, Republic of Korea. mkchung@kitox.re.kr
authors.forename: Moon Koo
authors.initials: MK
authors.lastname: Chung
authors.forename: Jong Choon
authors.initials: JC
authors.lastname: Kim
authors.forename: Won Bae
authors.initials: WB
authors.lastname: Kim
authors.forename: Kyung Koo
authors.initials: KK
authors.lastname: Kang
authors.forename: Sang Seop
authors.initials: SS
authors.lastname: Han
mesh_terms: 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
chemical_list: D011743:Pyrimidines; D013449:Sulfonamides; D013739:Testosterone; C419664:udenafil; D000096926:Benzenesulfonamides