초록 ▼

종근당 종합연구소에서는 3세대 성기능 개선제로서 다양한 구조-활성 연구와 구조-물성 연구, DMPK 및 독성 시험을 통하여 전임상 후보물질인 CKD-533을 선행연구결과 도출하였음. 본 과제에서 CKD-533의 비임상 시험완료를 위해 표준물질합성, 공정개선연구 및 시료규격설정 및 분석법을확립하였음. 그리고 임상진입을 위한 IND작성을 위한 자료를 구축하기 위해 물리화학적 특성연구, 기준 및 시험법 확립, 물리화학적 성상연구, 제제안정성연구, 단회투여 및 반복투여 독성시험, 유전독성시험, 안전성약리시험, 약동학 연구 등을 수행하였음.

종근당 종합연구소에서는 3세대 성기능 개선제로서 다양한 구조-활성 연구와 구조-물성 연구, DMPK 및 독성 시험을 통하여 전임상 후보물질인 CKD-533을 선행연구결과 도출하였음. 본 과제에서 CKD-533의 비임상 시험완료를 위해 표준물질합성, 공정개선연구 및 시료규격설정 및 분석법을확립하였음. 그리고 임상진입을 위한 IND작성을 위한 자료를 구축하기 위해 물리화학적 특성연구, 기준 및 시험법 확립, 물리화학적 성상연구, 제제안정성연구, 단회투여 및 반복투여 독성시험, 유전독성시험, 안전성약리시험, 약동학 연구 등을 수행하였음. 또한 추가연구를 수행하여 다양한 원인 (척추손상)의 발기부전과 전립선비대증으로 인한 과민성방광 치료제로서의 가능성도 확인하였음. 약동학 실험결과, 반복투여시 유의한 약물축적이 없었고 다른 PDE5 저해제와 비교시 생체내 반감기가 적절하였음. 반복투여 독성시험결과 임상 예측 용량과 비교 시 충분한 안전력을 가져 약물축적의 우려 없이 환자의 복용 편의성을 위한 1일1회 요법 특성을 갖추며 안전한제제로 평가되었음. 이러한 결과로부터 CKD-533의 개발가치가 충분하다고 판단하여 임상 1상 진입을 위한 IND를 2010년 상반기에 제출예정임.

Abstract ▼

Erectile dysfunction (ED) is a kind of disease that needs medical treatment. It is estimated that there are worldwide about 150 million patients in 2010 and about 300 million patients in 2025. In 2009, the market for ED is estimated at 80 billion won domestically and 4.3 billion dollars worldwide. A

Erectile dysfunction (ED) is a kind of disease that needs medical treatment. It is estimated that there are worldwide about 150 million patients in 2010 and about 300 million patients in 2025. In 2009, the market for ED is estimated at 80 billion won domestically and 4.3 billion dollars worldwide. As the 10% of the patients diagnosed with ED use drugs, rapid expansion of the market is estimated. Previously trazodone or yohimbine was prescribed as drugs for oral ED enhancer. However sildenafil (Viagra), PDE 5 inhibitor, was invented in 1998 and drew worldwide attention by its natural effect. Currently PDE5 inhibitors are being prescribed for ED of various causes. However sildenafil, the first generation medication, has severe side effects like vision disturbance, death, etc. and tadalafil, the second generation medication, frequently causes several side effects like myalgia or back pain. Therefore the development of new medication which has less side effect is certainly needed.
From the previous studies, CKD research institute discovered unique compounds of quinazoline backbone which have completely different chemical structure from that of currently marketed PDE 5 inhibitors (sildenafil, vardenafil, tadalafil). CKD-533, preclinical candidate compound, was selected through various structure-activity relationship, structure-property relationship, DMPK, toxicology study. From these results, CKD-533 was proven to have potent PDE5 inhibitory effect and better selectivity against other PDE subtype, expecially PDE6 and PDE11, which means no concern of side effects of vision disturbance and muscle pain. In addition, water solubility and oral absorption were excellent and outstanding in vivo efficacy was also proven.
The final goal of this study was to complete non-clinical study of CKD-533, the candidate compound and to submit IND for the entry into clinical phase. In order to accomplish those goals, following studies were performed. Standard compound synthesis, study for improvement of process, sample standard setting and establishment of analysis method were performed for non-clinical estimation of CKD-533. Then, physicochemical property study, establishment of specifications and analytical methods, physicochemical characteristics study, compound stability test, single dose toxicity study, multiple dose toxicity, genotoxicity, safety pharmacology and pharmacokinetics were performed to establish data needed for IND filing.
The possibility of CKD-533 as a medication for ED from various origins was confirmed through its superb efficacy in erectile dysfunction model by blood vessel obstruction and spinal cord
injury (additional study). In addition, The potential of CKD-533 as a medication for other urinary diseases like benign prostate hyperplasia and hyperactive bladder was confirmed through its superb efficacy in hyperactive bladder model induced by bladder obstruction. From the pharmacokinetics, significant drug accumulation was not observed in multiple dose and moderate half-life was observed compared to other PDE5 inhibitors. In addition, as being proven to have satisfactory safety margin compared to provisional clinical dose from multiple dose toxicity test, CKD-533 was estimated as a safe drug with beneficial aspects which can be dosed once a day for the convenience of patients without any concern of drug accumulation. Through these results, CKD research institute estimates that CKD-533 has enough value to be developed. Therefore we are going to submit IND for the entry into clinical phase 1 in the first half 2010.

목차 Contents

• 표지 ... 1
• 제출문 ... 3
• 보고서 요약서 ... 4
• 요약문 ... 5
• SUMMARY ... 6
• 6. 연구 성과 실적 및 향후 계획 ... 7
• 7. 참여연구원 현황표 ... 10
• 총괄연구과제 연구결과 ... 13
• 1. 연구개발과제의 배경 및 필요성 ... 14
• 2. 국내외 기술개발 현황 ... 16
• 3. 연구개발과제의 추진체계 ... 19
• 4. 연구개발수행 내용 및 결과 ... 21
• 5. 목표달성도 및 관련분야 기여도 ... 63
• 6. 향후 연구성과 추진 계획 ... 66
• 7. 연구개발결과의 파급효과 ... 67
• 8. 연구개발결과의 활용계획 ... 69
• 9. 연구개발과정에서 수집한 해외과학기술정보 ... 74
• 10. 참고문헌 ... 75
• 첨부서류 ... 76
• 끝페이지 ... 77