보고서 정보
주관연구기관 |
한국화학연구원 Korea Research Institute of Chemical Technology |
보고서유형 | 1단계보고서 |
발행국가 | 대한민국 |
언어 |
한국어
|
발행년월 | 2013-04 |
과제시작연도 |
2012 |
주관부처 |
미래창조과학부 Ministry of Science, ICT and Future Planning |
등록번호 |
TRKO201400022233 |
과제고유번호 |
1345168102 |
사업명 |
신약후보물질발굴및최적화사업 |
DB 구축일자 |
2014-11-10
|
키워드 |
당뇨.비만.후보물질 도출.치료제.대사성질환.diabetes.obesity.discovery of drug candidate.metabolic disease.
|
초록
▼
o DGAT1, GPR119, 11β-H SD 개발
- DGAT1 후보물질 도출 (KR69530) --> 기업에 라이센싱 완료함
- 11-H SD1 전임상 후보물질 1종 선정 및 backup 화합물 1종 확보
o DGAT1 저해제 개발
- 선행연구를 통하여 확보된 초기 유효물질에 대한 optimization연구를 수행 (1800여종합성)
- In vitro activity, selectivity assay , OLTT, OGTT 수행 (우수효과 확인)
- 화합물물성(solubility , permea
o DGAT1, GPR119, 11β-H SD 개발
- DGAT1 후보물질 도출 (KR69530) --> 기업에 라이센싱 완료함
- 11-H SD1 전임상 후보물질 1종 선정 및 backup 화합물 1종 확보
o DGAT1 저해제 개발
- 선행연구를 통하여 확보된 초기 유효물질에 대한 optimization연구를 수행 (1800여종합성)
- In vitro activity, selectivity assay , OLTT, OGTT 수행 (우수효과 확인)
- 화합물물성(solubility , permeability , chemical stability, plasmastability) 수행
- 약동력학 (CYP, metabolic stability , plasma protein binding, blood concentration, clearance, volume of distribution, oral bioavai lability ) 수행 (우수효과 확인)
- In vivo efficacy (triglyceride, body weight , plasma glucose) (우수효과 확인)
- Toxicity (hapatotoxicity , cytotoxicity , Herg, of ftarget select ivity , AMES, chromosome abberat ion, Micronucleus, single dose toxicity , 반복투여 독성 수행) (안정성확인)
o GPR119 조절제 개발
- 신규 화합물 460여종 합성
- 초기 후보물질인 KR69318을 도출 및 새로운 개념의 후속 화합물을 도출
o 11β-H SD1저해제 개발
- 선도물질 유도체 합성연구(화합물질 약 614종 합성)
- 약효 평가연구 : in vitro, in vivo, ex viv o 수행 / PK 평가연구 (Mouse, Dog, Monkey )
- 안전성 연구 : CYP 저해도 측정, 세포독성, hERG 저해평가, Safety & Liability Panel 수행, 단회투여독성연구, 2주 반복투여 독성연구 수행, 4주 반복투여독성연구 진행 중
- 전임상 시료 공정 개선 및 1.1 kg 생산
Abstract
▼
Several anti-diabetic and anti obese agents are currently available in the market, but the need for the new drug is extremely urgent due to the several side effects of existing drugs, insufficient therapeutic efficacy and rapidly increasing patients with a varety of pathoetiology. DGAT1, GPR119 and
Several anti-diabetic and anti obese agents are currently available in the market, but the need for the new drug is extremely urgent due to the several side effects of existing drugs, insufficient therapeutic efficacy and rapidly increasing patients with a varety of pathoetiology. DGAT1, GPR119 and 11β-HSD1 have received attention as they reduces body weight gain (obesity) and improve insulin sensitivity (diabetes).
Since 2010, we synthesized over 1800 new compounds as DGAT1 inhibitors, among them, KR69530 showed good profiles as a preclinical candidate. KR69530 showed a good in vitro inhibitory activity and good selectivity against DGAT2. In vivo (OLTT, orall ipid tolerance test) of KR69530 resulted in better TG reduction as compare to global top Novartis compound. KR69530 showed body weight gain reduction and glucose lowering efficacy after 4 weeks treatment DIO study. It exhibited no CYP inhibition, no Herg interaction, no cell cytotoxicity , no mutagenic potential , and LD50 > 1000 mpk in oral dosing. Also, It showed a good oral bioavailability. And finally, we successfully licensed out KR69530 to domestic pharmaceutical company. In conclusion, wed eveloped a new DGAT1 the preclinical cand idate, which will go into preclinical study. K00226 and K00516 compounds are another DGAT-1 candidates having in vitro, in vivo activity. We willtry advanced in vivo and toxicity study to develop preclinical candidates.
GPR119 agonists increase GLP-1 secretion from the gut and stimulateinsul in from beta-cell in the pancrease. We tried to identify a new GPR119 candidate and discovered lead compound, which is KR69318. It showed a good in vitro inhibitory activity with an IC50 of 2.9 nM and is metabolically stable in human and rat liver microsomes. KR69318 was evaluated in vivo for its glucose-lowering effect in normal mice. Oral administration of KR69318 at 15 mg/kg resulted in better glucose lowering than that of GSK1292263 30mg/kg. Also, it showed a good oral bioavailability. In conclusion, we developed a new GPR119 lead compound.
11β-HSD1 (11β-hyd roxy steroid dehydrogenase) is target to transfer inactive glucocorticoid to active form. If the 1β-HSD1 expression level increased, thet are related to some diseases such as obesity, insulin resistance, diabetes. UI-1544 is active in vitro and in vivo models. An then, we developed a new 11β-HSD1 lead compound
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