Subacute toxicity evaluation of KR-33493, FAF1 inhibitor for a new anti-parkinson's disease agent, after oral administration in rats and dogs.
KR33493, a newly developed FAS-associated factor 1 (FAF1) inhibitor for Parkinson's disease, is being evaluated in a Phase I clinical trial. In the present study, the subchronic toxicity of KR33493 in Sprague-Dawley (SD) rats and beagle dogs was investigated at various oral doses for 28 and 14 days, respectively. During the study, food consumption, body weights, organ weights, gross findings, and mortality were examined; and ophthalmoscopy, electrocardiography, hematology, serum biochemistry, urinalysis, histopathology, and toxicokinetics were performed. In rats, weight gain decreased in both sexes at 500 mg/kg/day, with no significant differences. In dogs, some significant differences compared with the control were found during the trial; however, at the end of recovery periods, these were no longer observed and there was no dose correlation. Some histopathological findings were observed, but these were considered as incidental changes. Since no other significant changes were observed, doses above 500 and 1000 mg/kg KR33493 in rat and dogs, respectively, caused no observed adverse effects. Therefore, based on these results, the Phase 1 clinical trial for KR33493 was approved by the Korean Food & Drug Administration.
Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, South Korea.
Jong-Woo
JW
Jeong
College of Biological Sciences and Biotechnology, Chungnam National University, Daejeon, South Korea.
Changsun
C
Yu
Research Center for General and Applied Toxicology, Korea Institute Toxicology, Daejeon, South Korea.
Jong-Hwa
JH
Lee
Research Center for General and Applied Toxicology, Korea Institute Toxicology, Daejeon, South Korea.
Kyoung-Sik
KS
Moon
Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, South Korea; College of Biological Sciences and Biotechnology, Chungnam National University, Daejeon, South Korea.
Eunhee
E
Kim
Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, South Korea. Electronic address: seyoo@cnu.ac.kr.
Sung-Eun
SE
Yoo
Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, South Korea. Electronic address: kootae@cnu.ac.kr.
Tae-Sung
TS
Koo
D000081:Acetamides / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D017321:Clinical Trials, Phase I as Topic; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000081:Acetamides; D048868:Adaptor Proteins, Signal Transducing; D000978:Antiparkinson Agents; C000621010:KR33493; D011720:Pyrazoles
FAF1 inhibitor; KR33493; NOAEL; Parkinson's disease; Phase 1 clinical trial; Subacute toxicity