Subacute toxicity evaluation of KR-33493, FAF1 inhibitor for a new anti-parkinson's disease agent, after oral administration in rats and dogs

• Published in: Regulatory toxicology and pharmacology 2016-11, Vol.81, p.387-396
• Main Authors: Jeong, Jong-Woo, Yu, Changsun, Lee, Jong-Hwa, Moon, Kyoung-Sik, Kim, Eunhee, Yoo, Sung-Eun, Koo, Tae-Sung
• Format: Article
• Language: English
• Subjects: Acetamides - administration & dosage; Acetamides - chemistry; Acetamides - toxicity; Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Administration, Oral; Animals; Antiparkinson Agents - administration & dosage; Antiparkinson Agents - chemistry; Antiparkinson Agents - toxicity; Clinical Trials, Phase I as Topic; Dogs; Dose-Response Relationship, Drug; FAF1 inhibitor; Female; KR33493; Male; NOAEL; Parkinson Disease - drug therapy; Parkinson's disease; Phase 1 clinical trial; Pyrazoles - administration & dosage; Pyrazoles - chemistry; Pyrazoles - toxicity; Rats; Rats, Sprague-Dawley; Subacute toxicity
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2016.09.022

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. •KR33493 can potentially be used to treat Parkinson's disease.•KR33493 is an FAS-associated factor 1 (FAF1) inhibitor.•The subchronic toxicity of KR33493 was determined in rats and dogs.•There were no adverse effects for tested doses in rats and dogs, respectively.•The phase 1 clinical trial was approved by the Korean FDA.