초록 ▼

1. AAD-2004 치매치료제 대형실용화사업은 2009.3월까지 임상 1상을 완료하고 1상 종료와 함께 2상 진입을 위한 준비완료를 과제의 목표로 함
2. 주관연구 기관의 연구내용 및 수행 내용의 결과
-전임상 및 임상연구를 위한 AAD-2004 의 대량 합성방법의 개발 및 합성단가 절약을 위한 공정개선:합성단계 단축, 단계별 수득률 향상시키는 공법의 개발로 대량합성 단가 절약
-back up 화합물의 발굴 및 합성:1차 7종 화합물 30 g 단위 합성하여 염증작용이 강화된 화합물 1종 도출, 2차:QSAR 에

1. AAD-2004 치매치료제 대형실용화사업은 2009.3월까지 임상 1상을 완료하고 1상 종료와 함께 2상 진입을 위한 준비완료를 과제의 목표로 함
2. 주관연구 기관의 연구내용 및 수행 내용의 결과
-전임상 및 임상연구를 위한 AAD-2004 의 대량 합성방법의 개발 및 합성단가 절약을 위한 공정개선:합성단계 단축, 단계별 수득률 향상시키는 공법의 개발로 대량합성 단가 절약
-back up 화합물의 발굴 및 합성:1차 7종 화합물 30 g 단위 합성하여 염증작용이 강화된 화합물 1종 도출, 2차:QSAR 에 의해 염증작용이 한층 강화된 화합물 수십종을 발굴,스크리닝 진행중
-임상 1상 진입을 위한 비임상 시험: 1상진입을 위한 1차년도 계획서상의90%이상 진행중
-동물모델에서 유효농도의 경구최적화:ALS및 stroke 동물모델에서 복강투여에 의한 세포사 보호 효과를 확인.(PK guided 경구최적화 진행중)
-치매동물쥐에서의 투여농도 및 기간설정,유효 혈중 유지농도 측정,투여시기 결정 등 임상 적용에 필요한 시험 실시 및 기전 연구: Tg2576, APP/PS1, APP/Tau 동물 모델을 이용한 상당수의 실험결과 확보
-위탁연구기관별 시험목적에따른 결과 수령

Abstract ▼

1.Purpose and significance
Alzheimer's disease(AD) is the most common cause of dementia among people age 65 and older. As a result of the rapid growth of the oldest age group-85 years and over-and of a decline in the death rate among persons over age 65, by 2030 nearly half the individuals with A

1.Purpose and significance
Alzheimer's disease(AD) is the most common cause of dementia among people age 65 and older. As a result of the rapid growth of the oldest age group-85 years and over-and of a decline in the death rate among persons over age 65, by 2030 nearly half the individuals with AD will be 85 years and older. The only drugs labeled to date for the treatment of cognitive symptoms in patients with AD are Aricept, cholinesterase inhibitors that prevent the breakdown of acetylcholine in the synapse and Memantine, NMDA antagonist. Both medications are associated with modest improvements in cognitive function. However, all benefit is lost when these drugs are discontinued:the disease then progresses to the level seen in placebo-treated patients. Thus drugs that are available for the treatment of AD are required to be developed. Drugs that are available for the treatment of AD can be divided into those whose actions enhance the effect of neurotransmitters and those thought to pr ot e ct n eu r ons an d th os e to b l oc k amyl oid p at ho l ogy . AAD-2004 is anti-oxidant and anti-inflammatory drug which are known to be a main pathological mechanisms leading to Aß production and cell death.AAD-2004 as a anti-alzheimer's drug development is funded by ministry of health and welfare from 2006 to 2008 finishing phase I clinical trial including non-clinical toxicity study of phase II
2.Contents of Study : In order to be a good drug, efficacy, safety, quality (physicochemical property) and formulation feasibility are very important
2-1.Efficacy study:Efficacy experiment in AD animal models such as Tg2576, APP/PS1, oxidative stress and cell death models such as ALS, Global Ischemia(GI) and inflammation models such as rheumatoid arthritis and acute pancreatitis models. In order to better translate preclinical animal study to clinical study, dose, period including dose starting time and duration will be studied. PK/PD study in efficacy animal models
2-2.Safety study:non-clinical toxicity study required for Phase I IND such as genotoxicity, safety pharmacology and single and multidose toxicity study in rodent and non-rodent was examined.
2-3.Manufacturing: Large quantity of active pharmaceutical ingredient (API) is required for non-clinical toxicity and efficacy study in animals
2-4.Process development study to shorten synthesis step and to lower large scale synthesis price
2-5.Continuous back-up search:Backups can be brought forward to replace a prototype that may fail during development and proceeded to enhance the chance of success toward clinical development. QSAR and continuous screening to have more strong anti-inflammation effects and good solubility
3.Study results
3-1.Efficacy study: AD model mice study: dose,treatment time and duration study was performed in Tg mice and got enough preclinical background data to better translate. Neuroprotection animal model mice study:Using ALS, GI model, efficacy was confirmed and now in the process of oral optimization in such animal models
3-2.Safety study: non-clinical toxicity studies required for phase I IND such as genotoxicity, safety pharmacology, single and repeated dose toxicity both in rodents and non-rodents were finished. Thus ready to prepare for IND leaving clinical formulation and clinical manufacturing which will be done in 2nd year
3-3.Process development and large scale synthesis: Successful process development enabled us to do large scale synthesis with lower price. API produced with new process were used for non-clinical toxicity study. Now it is under the study of impurity profiles
3-4.Back-up study: 1 backup compound which has better anti-inflammatory effects than AAD-2004 was selected through screening in acute pancreatitis inflammation animal model
3-5.Based on previous QSAR data with anti-oxidant and anti-inflammatory action moiety, more backup compounds are continuously designed,screened and now it is in its 3rd QSAR status toward final 5 candidates

목차 Contents

• 1.겉표지 ... 1
• 2. 제출문 ... 3
• 3. 보고서 요약서 ... 4
• 4.요약문 (한글) ... 5
• 5.요약문 (영문) ... 7
• 6. 연구 성과 실적 및 향후 계획 ... 9
• 7. 참여연구원 현황표 ... 30
• II. 총괄연구과제 연구결과 ... 32
• 1. 연구개발과제의 배경 및 필요성 ... 33
• 2. 국내외 기술개발 현황 ... 40
• 3. 연구개발과제의 추진체계 ... 48
• 4. 연구개발수행 내용 및 결과 ... 50
• 5. 목표달성도 및 관련분야 기여도 ... 419
• 6. 향후 연구성과 추진 계획 ... 421
• 7. 연구개발결과의 파급효과 ... 421
• 8. 연구개발결과의 활용계획 ... 424
• 9. 연구개발과정에서 수집한 해외과학기술정보 ... 430
• 10. 참고문헌 ... 436
• IV.제1세부연구과제연구결과 ... 437
• IV. 첨부서류 ... 439
• 1. 자체평가의견서 ... 440
• 2. 연구성과 실적 증빙서류 ... 445
• 3. 기타 요청서류 ... 445