KR101888578B1 - A pharmaceutical composition for promoting osteogenesis comprising thiacremonone - Google Patents
A pharmaceutical composition for promoting osteogenesis comprising thiacremonone Download PDFInfo
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- KR101888578B1 KR101888578B1 KR1020170037117A KR20170037117A KR101888578B1 KR 101888578 B1 KR101888578 B1 KR 101888578B1 KR 1020170037117 A KR1020170037117 A KR 1020170037117A KR 20170037117 A KR20170037117 A KR 20170037117A KR 101888578 B1 KR101888578 B1 KR 101888578B1
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- bone
- pharmaceutical composition
- osteoporosis
- acid
- osteoclast differentiation
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Abstract
Description
본 발명은 마늘에서 유래한 신규 화합물을 함유하는 인체 안전성이 우수한 골형성 촉진용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition containing a novel compound derived from garlic and having excellent human safety and promoting bone formation.
뼈는 일생동안 지속적으로 변화하는 활동적인 조직이다. 뼈는 육안으로 외부의 피질골(치밀골)과 내부의 소주골(해면골, 스폰지뼈)로 구분하는데, 피질골은 물리적인 강도가 강하여 신체를 보호하고 지지하는 역할을 하고, 소주골은 충격을 흡수하거나 칼슘의 변화를 일정하게 유지하는 역할을 주로 한다.Bones are an active organization that constantly changes throughout their lives. The bones are divided into the outer cortical bone (fine bone) and the inner soochu bone (spongy bone, sponge bone) by the naked eye. The cortical bone has a strong physical strength to protect and support the body. And to maintain a constant change of.
뼈의 성장이 중단된 후에도 오래된 뼈는 파괴되어 없어지고(골 흡수), 새로운 뼈가 없어진 곳을 메우는 고정(골형성)이 일생동안 반복되는, 이러한 현상을 뼈의 재형성(remodeling)이라 한다. 조골세포와 파골세포 사이의 상호작용이 균형을 이루어 골 흡수와 골형성이 균형을 이루어야 뼈의 항상성이 유지되고 혈액 속의 칼슘 농도가 일정하게 유지되는데, 혈액에 칼슘이 부족하게 되면 이를 보충하기 위하여 골 흡수가 증가되어 뼈의 칼슘을 혈액으로 방출하게 되며, 골 흡수가 지속되면 뼈가 약해져 골다공증과 같은 질환이 발생한다.This phenomenon is called bone remodeling, in which the old bone is destroyed and disappeared (bone resorption) and the fixation (osteogenesis) to fill the void of new bone is repeated throughout its lifetime, even after bone growth has ceased. The balance between osteoblast and osteoclast is balanced so that bone resorption and osteogenesis are balanced so that bone homeostasis is maintained and the calcium concentration in the blood is kept constant. When calcium is lacking in the blood, The absorption is increased to release the calcium of the bone into the blood. If the bone resorption continues, the bone is weakened and the disease such as osteoporosis occurs.
특히, 골다공증은 폐경에 따른 급격한 호르몬의 변화에 의한 파골세포(osteoclast)의 활성화에 따른 골흡수 증가로 나타나는 폐경 후 골다공증과, 노화가 되면서 조골세포(osteoblast)의 기능이 감소하여 골형성이 감소하는 노인성 골다공증으로 분류할 수 있다. 이러한 골다공증으로 인한 골절은 심각한 활동 제한에 이르게 되고, 고관절 골절의 경우 약 15-35%의 높은 사망률과 관련되어 있기 때문에, 골다공증성 골절이 발생하기 이전에 골다공증의 진단과 치료가 중요하다.Particularly, osteoporosis is caused by postmenopausal osteoporosis, which is caused by an increase in bone resorption due to activation of osteoclast due to rapid hormone change due to menopause, and decreased osteoblast function due to decrease of osteoblast function in aging It can be classified as geriatric osteoporosis. Diagnosis and treatment of osteoporosis is important before osteoporotic fractures occur, since fractures due to these osteoporosis lead to severe limitation of activity and high fracture rates are associated with a high mortality rate of about 15-35%.
세계보건기구(WHO)에 따르면 미국에서 폐경기 이후 여성의 약 30%가 골다공증에 걸려있으며, 약 50%가 골감소증의 현상을 보이고 있고, 약 2,600만 명이 골다공증에 의한 골절 위험성을 내재하고 있는 것으로 보고되고 있다. 또한, 미국에서 이들 골다공증 환자는 매년 약 2%씩 증가할 것으로 예상되고 급속한 노령화가 진행되는 국내에서도 골다공증 환자가 급증하고 있다.According to the World Health Organization (WHO), about 30% of post-menopausal women in the United States have osteoporosis, about 50% have osteopenia, and about 26 million people have osteoporotic fractures have. In the United States, these osteoporosis patients are expected to increase by about 2% each year. In Korea where rapid aging is taking place, osteoporosis patients are increasing rapidly.
골다공증 치료제는 골 흡수 저해제(antiresorptive drug)와 골형성 촉진제로 분류된다. 골 흡수 저해제는 파골세포의 형성과 활성을 조절하는 치료제로서 비스포스포네이트, 선택적 에스트로겐 수용체 조절자(SERMs), 칼시토닌 등이 있으며, 골형성 촉진제로서는 부갑상선 호르몬제(PTH), 불소제 등이 있다. 골다공증 치료제 시장에서 가장 큰 시장을 차지하고 있는 비스포스포네이트 치료제는 식전 공복에 복용해야 하고 복용시 식도염, 식도 천공 등의 부작용이 발생하며 체내 흡수율이 낮다는 단점이 있다. 선택적 에스트로겐 수용체 조절자로는 라록시펜, 드롤록시펜, 라소폭시펜 등이 있으나, 이들 치료제는 유방암 및 자궁암 유발 위험성을 증가시키는 부작용이 있다. 또한, 칼시토닌 치료제는 고가이며 투여방법이 어렵고 칼슘 제제는 부작용은 적지만 골다공증 치료보다는 예방에 국한된다는 단점이 있다.Osteoporosis treatments are classified as antiresorptive drugs and bone formation promoters. Bone resorption inhibitors include bisphosphonates, selective estrogen receptor modulators (SERMs), calcitonin, and the like, and parathyroid hormone (PTH) and fluoride agents are examples of therapeutic agents for controlling osteoclast formation and activity. Bisphosphonate, which is the biggest market in the osteoporosis treatment market, has a disadvantage in that it needs to be taken on an empty stomach and has side effects such as esophagitis and esophageal perforation. Selective estrogen receptor modulators include, but are not limited to, raloxifene, droloxifene, and lasofoxifene, which have side effects that increase the risk of breast and uterine cancer induction. Calcitonin is expensive and difficult to administer, and calcium preparations have few side effects but are limited to prevention rather than osteoporosis treatment.
현재까지 개발된 골다공증 치료제들은 부갑상선 호르몬제를 제외하고는 골형성 작용이 미미하여 치료효과보다는 증상의 진행을 예방하는 효과에 그치고 있다. 또한, 골형성 효과를 갖는 부갑상선 호르몬제의 경우는 골형성을 촉진하여 치료효과를 얻을 수 있지만 장기 사용에 대한 안전성이 확립되지 않아 그 사용이 제한되고 있다. The osteoporosis medicines developed so far have only a limited effect on osteogenesis except for the parathyroid hormone, so that they prevent the progress of the symptoms rather than the treatment effect. In addition, the parathyroid hormone agent having an osteogenesis effect promotes osteogenesis to obtain a therapeutic effect, but its safety is not established for long-term use and its use is limited.
한편, 마늘은 황(sulfur) 및 셀레노(seleno) 화합물을 포함하여 다양한 약리학적 활성성분을 함유하고 있기 때문에, 의학적 용도로서 잠재적 특성에 대한 관심이 집중되고 있다. On the other hand, since garlic contains a variety of pharmacologically active ingredients, including sulfur and seleno compounds, attention has been focused on potential properties for medical use.
치아크레모논(thiacremonone)은 최근 마늘에서 분리된 유황화합물로서, 다양한 생리활성 및 약학적 효과가 보고된 바 있으나 뼈 재흡수 세포에서의 역할은 알려진 바 없다.Thiacremonone has recently been reported as a sulfur compound isolated from garlic, and its various physiological activities and pharmacological effects have been reported, but its role in bone resorbing cells is unknown.
본 발명자들은 골 질환에 수반되는 파골세포의 형성을 억제하는 저분자 화합물 개발을 위한 연구를 진행하였으며, 치아크레모논의 파골세포 특이적 활성을 규명함으로써 골 질환의 예방 및 치료 용도로서 활용하고자 하였다.The present inventors have conducted research for the development of a low molecular compound that inhibits the formation of osteoclasts accompanied by bone diseases and have tried to utilize osteoclasts as a prophylactic and therapeutic treatment of osteopathy by examining the osteoclast specific activity.
본 발명은 전술한 종래기술의 문제점을 해결하기 위하여 인체 안전성이 우수할 뿐만 아니라 파골세포의 분화를 선택적으로 억제하는 신규 화합물을 제공하는 것을 목적으로 한다.It is an object of the present invention to provide a novel compound which not only has excellent human safety but also selectively inhibits osteoclast differentiation in order to solve the above problems of the prior art.
또한, 본 발명은 상기 신규 화합물을 포함하는 골 질환 예방 및 치료용 조성물을 제공하는 것을 목적으로 한다.It is another object of the present invention to provide a composition for preventing and treating bone diseases, which comprises the novel compound.
본 발명의 일 측면에 따르면, 하기 화학식 1의 화합물 또는 그의 약제학적으로 허용 가능한 염을 유효 성분으로 포함하는 골형성 촉진용 약학적 조성물이 제공된다.According to one aspect of the present invention, there is provided a pharmaceutical composition for promoting bone formation comprising a compound of the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Chemical Formula 1]
일 실시예에 있어서, 상기 화학식 1의 화합물은 마늘에서 단리될 수 있다.In one embodiment, the compound of
일 실시예에 있어서, 상기 조성물은 RANKL(Receptor activator of NK-κB ligand)에 의해 유도되는 파골세포 분화를 억제할 수 있다.In one embodiment, the composition may inhibit osteoclast differentiation induced by RANKL (Receptor activator of NK-κB ligand).
일 실시예에 있어서, 상기 조성물은 조골세포 분화에 영향을 미치지 않을 수 있다.In one embodiment, the composition may not affect osteoblast differentiation.
일 실시예에 있어서, 상기 조성물은 골 질환 예방 또는 치료용일 수 있다.In one embodiment, the composition may be for preventing or treating bone disease.
일 실시예에 있어서, 상기 골 질환은 골다공증, 골형성 부전증, 골연화증, 골량 감소증, 골절, 골 결손 및 고관절 감소증으로 이루어진 군으로부터 하나 이상 선택될 수 있다.In one embodiment, the bone disease may be selected from the group consisting of osteoporosis, osteoporosis, osteomalacia, osteopenia, fracture, bone defect, and hip arthropathy.
일 실시예에 있어서, 상기 조성물은 인공골, 인공관절, 골 고정재, 골 대체제, 골 수복재, 골 충진재 및 골 이식재로 이루어진 군으로부터 선택된 하나 이상의 물질에 사용될 수 있다.In one embodiment, the composition may be used in one or more materials selected from the group consisting of artificial bone, artificial joint, bone fixation, bone substitute, bone restoration, bone filler and bone graft material.
본 발명의 다른 측면에 따르면, 하기 화학식 1의 화합물 또는 그의 식품학적으로 허용 가능한 염을 유효 성분으로 포함하는 골 질환 예방 또는 개선용 건강기능식품이 제공된다.According to another aspect of the present invention, there is provided a health functional food for preventing or ameliorating bone diseases, which comprises a compound of the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Chemical Formula 1]
본 발명에 따르면, 상기 골형성 촉진용 조성물은 천연 식물 유래의 화합물을 포함하여 체내 독성이 낮고 파골세포의 분화를 선택적으로 억제하므로 골 질환 예방 및 치료에 유용하게 활용될 수 있다. According to the present invention, the composition for promoting osteogenesis, including a compound derived from a natural plant, has low toxicity in the body and selectively inhibits osteoclast differentiation, and thus can be usefully used for prevention and treatment of bone diseases.
본 발명의 효과는 상기한 효과로 한정되는 것은 아니며, 본 발명의 상세한 설명 또는 특허청구범위에 기재된 발명의 구성으로부터 추론 가능한 모든 효과를 포함하는 것으로 이해되어야 한다.It should be understood that the effects of the present invention are not limited to the above effects and include all effects that can be deduced from the detailed description of the present invention or the configuration of the invention described in the claims.
도 1은 치아크레모논의 파골세포에 대한 세포독성을 분석한 것이다. (A) 치아크레모논의 화학적 구조를 나타낸 것이다. (B) 1, 10, 30 및 100 μM의 치아크레모논을 24시간 동안 처리한 것이다. (C, D) 100 ng/mL의 RANKL의 존재하에 치아크레모논을 처리하고 3일 및 5일 동안 배양한 것이다.
도 2는 치아크레모논의 RANKL 매개 파골세포 유전자 발현 및 TRAP-양성 MNC에 대한 효과를 분석한 것이다. (A, B) 10 및 30μM의 치아크레모논을 처리하고 3일 동안 30 ng/mL의 MCSF 및 100 ng/mL의 RANKL와 함께 BMM을 배양한 후 qRT-PCR을 통해 c-Fos 및 NF-ATc1을 분석한 것이다. (C, D) 10 및 30μM의 치아크레모논을 처리하고 5일 동안 30 ng/mL의 MCSF 및 100 ng/mL의 RANKL와 함께 BMM을 배양한 후 TRAP 스테이닝한 결과이다.
도 3은 치아크레모논의 RANKL 매개 F-actin ring formation에 대한 효과를 분석한 것이다. (A, B) F-actin 링 형성은 FITC-phalloidin(녹색) 및 DAPI (청색)으로 스테이닝한 후 형광 현미경으로 관찰하였다.
도 4는 두개관 전-조골세포 및 파골세포에서 치아크레모논의의 세포독성을 분석한 것이다. (A) 두개관 전-조골세포에 치아크레모논을 24시간 동안 처리한 것이다. (B) 골 형성 보충 배지(OS)에서 치아크레모논을 처리하고 배양한 것이다.
도 5는 마우스 초대 두개관 전-조골세포에서 치아크레모논의 조골세포 분화에 대한 효과를 분석한 것이다. (A) ALP 활성을 측정한 것이다. (B) ARS(Alizarin red S) 스테이닝 결과이다.
도 6은 치아크레모논의 작용 기작을 도식화 한 것이다. FIG. 1 is an analysis of cytotoxicity against osteoclasts in dental crestoma. (A) The chemical structure of the tooth crème. (B) 1, 10, 30 and 100 μM of tetracammonium for 24 hours. (C, D) 100 ng / mL of RANKL and cultured for 3 and 5 days.
FIG. 2 is an analysis of the effect of RANKL mediated osteoclast gene expression and TRAP-positive MNC on dacrycoma. (A,
FIG. 3 is an analysis of the effect of RANKL mediated F-actin ring formation in dental cremophoresis. (A, B) F-actin ring formation was stained with FITC-phalloidin (green) and DAPI (blue) and then observed with fluorescence microscope.
Fig. 4 is an analysis of cytotoxicity of dacrycomonon in two osteoclast and osteoclast cells. (A) Two open-loop osteoblasts treated with dicamcone for 24 h. (B) Tissue crmmonium was treated and cultured in osseous supplemented medium (OS).
FIG. 5 is a graph showing the effect of osteoblast differentiation on osteoblast differentiation in mouse osteoblasts. (A) ALP activity. (B) ARS (Alizarin red S) staining results.
Figure 6 is a schematic representation of the mechanism of action of dia. Cremoron.
이하에서는 첨부한 도면을 참조하여 본 발명을 설명하기로 한다. 그러나 본 발명은 여러 가지 상이한 형태로 구현될 수 있으며, 따라서 여기에서 설명하는 실시예로 한정되는 것은 아니다. 어떤 부분이 어떤 구성요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 구비할 수 있다는 것을 의미한다.DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described with reference to the accompanying drawings. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. When an element is referred to as " comprising ", it means that it can include other elements, not excluding other elements unless specifically stated otherwise.
달리 정의되지 않는 한, 분자 생물학, 미생물학, 단백질 정제, 단백질 공학, 및 DNA 서열 분석 및 당업자의 능력 범위 안에서 재조합 DNA 분야에서 흔히 사용되는 통상적인 기술에 의해 수행될 수 있다. 상기 기술들은 당업자에게 알려져 있고, 많은 표준화된 교재 및 참고저서에 기술되어 있다.Unless otherwise defined, can be performed by molecular biology, microbiology, protein purification, protein engineering, and DNA sequencing and routine techniques commonly used in the art of recombinant DNA within the skill of those skilled in the art. These techniques are known to those skilled in the art and are described in many standardized textbooks and references.
본 명세서에 포함되는 용어를 포함하는 다양한 과학적 사전이 잘 알려져 있고, 당업계에서 이용가능하다. 본 명세서에 설명된 것과 유사 또는 등가인 임의의 방법 및 물질이 본원의 실행 또는 시험에 사용되는 것으로 발견되나, 몇몇 방법 및 물질이 설명되어 있다. 당업자가 사용하는 맥락에 따라, 다양하게 사용될 수 있기 때문에, 특정 방법학, 프로토콜 및 시약으로 본 발명이 제한되는 것은 아니다. Various scientific dictionaries, including the terms contained herein, are well known and available in the art. Although any methods and materials similar or equivalent to those described herein are found to be used in the practice or testing of the present application, some methods and materials have been described. It is not intended that the invention be limited to the particular methodology, protocols, and reagents, as they may be used in various ways in accordance with the context in which those skilled in the art use them.
본 명세서에서 사용되는 바와 같이, 단수형은 문맥이 명확하게 달리 지시하지 않으면 복수의 대상을 포함한다. 또한, 달리 지시된 바가 없으면, 핵산은 각각 왼쪽에서 오른쪽, 5'에서 3' 방향으로 씌여지고, 아미노산 서열은 왼쪽에서 오른쪽, 아미노에서 카르복실 방향으로 씌여진다. 이하 본 발명을 더욱 상세히 설명한다. As used herein, the singular forms include plural objects unless the context clearly dictates otherwise. Also, unless otherwise indicated, nucleic acids are written from left to right, 5 'to 3', amino acid sequences from left to right, amino to carboxyl. Hereinafter, the present invention will be described in more detail.
본 발명의 일 측면에 따르면, 하기 화학식 1의 화합물 또는 그의 약제학적으로 허용 가능한 염을 유효 성분으로 포함하는 골형성 촉진용 약학적 조성물이 제공된다.According to one aspect of the present invention, there is provided a pharmaceutical composition for promoting bone formation comprising a compound of the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Chemical Formula 1]
상기 화학식 1의 화합물은 "치아크레모논(thiacremonone)"으로 호칭될 수 있다. 상기 "치아크레모논"은 가열 처리한 마늘에 분획된 항산화 활성을 갖는 화합물이다(Kwon OC, Woo KS, Kim TM, Kim DJ, Hong JT, Jeong HS. Korean J Food Sci Technol. 2006; 38:331-336). 상기 치아크레모논 화합물은 균류인 Acremonium sp . 균주 HA33-95가 생하는 것으로 알려져 있으며, 항암활성, 염증성 질환 및 당뇨, 고지혈증 및 심혈관 질환과 같은 대사성 질환에 대한 치료 효과가 보고된 바 있으나, 골형성 촉진 활성 또는 파골세포 분화에 대한 억제 활성은 아직 보고된 바 없다.The compound of
상기 화합물은 약제학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 상기 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용할 수 있다. 상기 화합물은 당해 기술 분야에서 통상적인 방법에 따라 약제학적으로 허용되는 산 부가염을 형성할 수 있다. 유리산은 유기산 및 무기산이 사용될 수 있으며, 예컨대, 상기 무기산은 염산, 브롬산, 황산, 또는 인산 일 수 있으며, 상기 유기산은 구연산(Citric acid), 초산, 젖산, 주석산(Tartaric acid), 말레인산, 푸마르산(Fumaric acid), 포름산, 프로피온산(Propionic acid), 옥살산, 트리플루오로아세트산, 벤조산, 글루콘산, 메탄설폰산, 글리콜산, 숙신산(Succinic acid), 4-톨루엔설폰산, 벤젠설폰산, 살리실산, 니코틴산, 이소니코틴산, 피콜린산, 글루탐산 또는 아스파르트산일 수 있으나, 이에 제한되는 것은 아니다.The compound may be used in the form of a pharmaceutically acceptable salt, and the salt may be an acid addition salt formed by a pharmaceutically acceptable free acid. Such compounds may form pharmaceutically acceptable acid addition salts according to methods conventional in the art. The free acid may be an organic acid or an inorganic acid. For example, the inorganic acid may be hydrochloric acid, bromic acid, sulfuric acid, or phosphoric acid. The organic acid may be citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid But are not limited to, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4- toluenesulfonic acid, benzenesulfonic acid, Nicotinic acid, isonicotinic acid, picolinic acid, glutamic acid, or aspartic acid.
상기 조성물은 RANKL(Receptor activator of NK-κB ligand)에 의해 유도되는 파골세포 분화를 억제할 수 있고, 조골세포 분화에는 영향을 미치지 않을 수 있다.The composition may inhibit osteoclast differentiation induced by RANKL (Receptor activator of NK-虜 B ligand) and may not affect osteoblast differentiation.
상기 RANKL은 파골세포 전구체 상에 발현되는 RANK 수용체에 결합하여, MAPK 경로를 포함한 다양한 신호 경로를 활성화하고, c-Fos 및 NFATc1와 같은 전사인자를 조절할 수 있다. The RANKL binds to RANK receptors expressed on osteoclast precursors to activate various signal pathways including the MAPK pathway and to control transcription factors such as c-Fos and NFATc1.
상기 치아크레모논은 RANKL에 의해 자극된 BMM 파골전구세포에서 파골세포 발생과 관련된 전사인자, c-Fos 및 NFATc1의 발현 수준을 선택적으로 감소시킬 수 있음에도 불구하고, 조골세포의 분화에는 영향을 미치지 아니할 수 있다.Although the above-mentioned dicryptone can selectively reduce the expression level of transcription factors related to osteoclastogenesis, c-Fos and NFATc1 in RANKL-stimulated BMM osteoclast precursor cells, it does not affect the osteoblast differentiation .
즉, 통상적으로 골 형성을 촉진하는 물질의 경우 파골세포의 분화를 억제함과 동시에, 조골세포의 분화를 촉진시킴으로써 골 형성을 촉진할 수 있었으나, 상기 치아크레모논은 파골세포의 분화만을 선택적으로 억제하므로 질병의 증상이나 환자의 특성에 따라 유용하게 활용 가능하다.In other words, in the case of a substance promoting osteogenesis, osteoclastogenesis can be promoted by inhibiting osteoclast differentiation and promoting differentiation of osteoblast cells, but the dental crmmonone selectively inhibits osteoclast differentiation only Therefore, it can be usefully used depending on the symptoms of the disease or the characteristics of the patient.
상기 화학식 1의 화합물은 마늘(Allium sativum)을 물 또는 유기용매로 추출하여 수득한 추출물에서 단리될 수 있고, 상기 추출 방법을 특별히 제한되지 않으나 물, 탄소수 1 내지 6의 알코올, 핵산, 클로로포름, 메틸아세테이트, 또는 부탄올을 용매로 하여 추출될 수 있다.The compound of
에컨대, 상기 마늘은 알코올로 추출될 수 있다. 상기 알코올은 탄소수 1 내지 6의 지방족 알코올 일 수 있으며, 구체적으로는 메탄올, 에탄올, 이소프로판올, 부탄올, 헥산 등이 사용될 수 있으나, 이에 한정되지 않는다.For example, the garlic may be extracted with alcohol. The alcohol may be an aliphatic alcohol having 1 to 6 carbon atoms, and specifically, methanol, ethanol, isopropanol, butanol, hexane and the like may be used, but the present invention is not limited thereto.
상기 알코올 추출물은 유기용매 및 물로 분배 추출될 수 있다. 상기 유기용매는 탄소수 1 내지 10의 지방족 탄화수소, 탄소수 1 내지 10의 지방족 할로겐화 탄화수소 및 탄소수 2 내지 10의 에스테르 중에서 선택될 수 있으나, 바람직하게는 에틸아세테이트를 사용할 수 있다.The alcohol extract may be dispensed into an organic solvent and water. The organic solvent may be selected from aliphatic hydrocarbons having 1 to 10 carbon atoms, aliphatic halogenated hydrocarbons having 1 to 10 carbon atoms, and esters having 2 to 10 carbon atoms, preferably ethyl acetate.
상기 분배 추출된 에틸아세테이트 분획은 실리카 겔 컬럼 크로마토그래피를 통해 분리될 수 있다. 상기 실리카 겔 컬럼 크로마토그래피는 n-헥산 및 다이클로로메탄의 혼합액을 용리액으로 사용할 수 있으며, 상기 혼합액의 부피비는 20:1 에서 2:1까지 순차적으로 할 수 있다.The fractionally extracted ethyl acetate fraction can be separated through silica gel column chromatography. The silica gel column chromatography can use a mixed solution of n-hexane and dichloromethane as an eluent, and the volume ratio of the mixed solution can be sequentially adjusted from 20: 1 to 2: 1.
상기 실리카 겔 컬럼 크로마토그래피에 의해 수득된 용출액은 n-헥산 및 다이클로로메탄을 용리액(1:2 내지 1:3 부피비)으로 사용하여 실리카 겔 컬럼 크로마토그래피를 재차 수행할 수 있으며, 상기 수득된 용출액은 n-헥산 및 에틸아세테이트를 용리액(3:1 내지 5:1 부피비)으로 사용하여 최종적으로 상기 화합물이 수득될 수 있다.The eluate obtained by the silica gel column chromatography can be subjected to silica gel column chromatography again using n-hexane and dichloromethane as an eluent (1: 2 to 1: 3 by volume), and the obtained eluate Using n-hexane and ethyl acetate in the eluent (3: 1 to 5: 1 by volume ratio), finally the compound can be obtained.
상기 조성물은 골 질환 예방 또는 치료용일 수 있고, 상기 골 질환은 대사성 골 질환 또는 정형외과적 골 질환일 수 있다.The composition may be for prevention or treatment of bone disease, and the bone disease may be metabolic bone disease or orthopedic bone disease.
상기 “대사성 골 질환”은 파골세포의 과다한 생성 또는 활성으로 인해 나타나는 상태 또는 질병을 의미하는 것으로, 골량 저하 질환을 포함할 수 있다. 상기 골량 저하 질환이란 골밀도의 저하, 골조직의 연화 등의 증상을 수반하는 골량의 저하가 나타나는 상태 또는 질환을 의미한다.The above-mentioned " metabolic bone disease " means a condition or disease caused by excessive production or activity of osteoclasts, and may include bone loss diseases. The term "lowering bone disease" refers to a condition or disease in which a decrease in bone mass accompanying symptoms such as a decrease in bone density and softening of bone tissue occurs.
상기 골 질환은 골다공증, 골형성 부전증, 골연화증, 골량 감소증, 골절, 골 결손 및 고관절 감소증으로 이루어진 군으로부터 하나 이상 선택될 수 있으나, 이에 한정되는 것은 아니다.The bone disease may be selected from the group consisting of osteoporosis, osteoarthritis, osteomalacia, osteopenia, fracture, bone defect and hip joint hypoplasia, but is not limited thereto.
상기 조성물은 인공골, 인공관절, 골 고정재, 골 대체제, 골 수복재, 골 충진재 및 골 이식재로 이루어진 군으로부터 선택된 하나 이상의 물질에 사용될 수 있다.The composition may be used in one or more materials selected from the group consisting of artificial bone, artificial joint, bone fixation material, bone substitute, bone restoration material, bone filler and bone graft material.
상기 골형성 촉진용 조성물은 골 질환 또는 치주질환의 예방 및 치료용으로 사용될 수 있으며, 인공골, 골 고정재, 골 대체제, 골 수복재, 골 충진재 또는 골 이식재에 적용되기 용이한 형태로 제조될 수 있다.The composition for promoting bone formation can be used for prevention and treatment of bone disease or periodontal disease and can be manufactured in a form that can be easily applied to artificial bone, bone fixation material, bone substitute, bone restoration material, bone filler or bone graft material .
예컨대, 상기 골 이식재나 골 대체체는 협의로는 골 조직 내의 공간을 충진하기 위하여 사용될 수도 있고, 광의로는 뼈나 치아의 일부를 대체하는데 사용될 수 있으므로, 상기 골형성 촉진용 조성물은 압착, 압축, 가압접촉, 패킹, 압박, 굳힘 등의 방법을 사용하여 퍼티, 페이스트, 주형 가능한 스트립, 블록, 칩 등의 형태로 사용될 수 있고, 화학적 첨가물을 이용하여, 겔, 과립, 페이스트, 정제, 펠렛 등의 형태로 제형화하여 사용될 수 있으며, 분말 형태로도 사용될 수 있다.For example, the bone graft material or the bone substitute can be used to fill a space in the bone tissue in a narrow sense, and can be used to replace a part of a bone or a tooth in a broad sense. Therefore, Can be used in the form of a putty, a paste, a moldable strip, a block, a chip or the like by using a method of pressurized contact, packing, pressing or hardening, and the chemical additives can be used to form a gel, a granule, a paste, a tablet, And may be used in powder form.
상기 조성물은 경구적 전달, 비경구적 전달의 형태로 투여될 수 있다. 상기 조성물은 전신 또는 국소 투여될 수 있으며, 상기 투여는 경구 투여 및 비경구 투여를 포함할 수 있다. 상기 조성물은 적절한 투여 형태를 제공하도록 적합한 양의 약학적으로 허용되는 비히클 또는 담체와 함께 제형화될 수 있다.The compositions can be administered in the form of oral delivery, parenteral delivery. The composition may be administered systemically or topically, and the administration may include oral administration and parenteral administration. The composition may be formulated with a suitable amount of a pharmaceutically acceptable vehicle or carrier to provide a suitable dosage form.
상기 화합물을 포함하는 조성물은 약학 조성물의 제조에 사용되는 담체, 부형제 및 희석제를 더 포함할 수 있다.The composition comprising the compound may further comprise a carrier, an excipient and a diluent which are used in the production of the pharmaceutical composition.
상기 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유를 들 수 있으나, 이에 한정되는 것은 아니다.Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, But are not limited to, cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.
또한, 상기 조성물은 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제제화 하여 사용할 수 있다.In addition, the composition may be formulated in the form of oral, granule, tablet, capsule, suspension, emulsion, syrup, aerosol or the like, external preparation, suppository and sterilized injection solution.
경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 화합물에 적어도 하나 이상의 부형제, 예컨대, 전분, 칼슘카보네이트, 수크로스, 락토오스, 또는 젤라틴 등을 혼합하여 조제할 수 있다. 또한, 상기 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제가 사용될 수 있다.Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatin, Can be mixed and prepared. In addition to the above excipients, lubricants such as magnesium stearate and talc may be used.
경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 사용될 수 있으며, 단순희석제인 물, 리퀴드 파라핀 외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.As the liquid preparation for oral administration, suspensions, solutions, emulsions, syrups and the like may be used. In addition to water and liquid paraffin which are simple diluents, various excipients such as wetting agents, sweeteners, fragrances and preservatives may be included .
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 사용될 수 있다. 상기 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르가 사용될 수 있다. 상기 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴이 사용될 수 있다.For parenteral administration, sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories may be used. Examples of the non-aqueous solvent and suspensions may include injectable esters such as propylene glycol, polyethylene glycol, vegetable oil such as olive oil and ethyl oleate. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, and glycerogelatin.
본 발명의 다른 측면에 따르면, 하기 화학식 1의 화합물 또는 그의 식품학적으로 허용 가능한 염을 유효 성분으로 포함하는 골 질환 예방 또는 개선용 건강기능식품이 제공된다.According to another aspect of the present invention, there is provided a health functional food for preventing or ameliorating bone diseases, which comprises a compound of the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Chemical Formula 1]
상기 건강기능식품은 건강기능식품에 관한 법률에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미할 수 있으며, 상기 기능성은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미할 수 있으나, 건강의 개선을 위한 목적으로 섭취하는 식품이라면 그 종류가 특별히 제한되는 것은 아니다.The health functional food may refer to a food prepared or processed by using a raw material or ingredient having useful functionality according to the Health Functional Food Act, and the functional property may be adjusted by controlling nutrients with respect to the structure and function of the human body Physiological activity, etc., but the type of the food to be ingested for the purpose of improving health is not particularly limited.
상기 건강기능식품은 정제, 과립, 분말, 캅셀, 액상의 용액 및 환으로 이루어진 군에서 선택된 어느 하나의 제형으로 제조될 수 있다.The health functional food may be prepared in any one form selected from the group consisting of tablets, granules, powders, capsules, liquid solutions and rings.
상기 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 상기 식품 첨가물은 다른 규정이 없는 한 식품의약품 안정청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 적합성 여부를 판단할 수 있다. 상기 식품 첨가물 공전에 기재된 품목은 예컨대 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성물, 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류를 들 수 있다.The above-mentioned health functional foods may contain usual food additives, and, unless otherwise specified, the above-mentioned food additives are classified according to the standard and the standard of the relevant items according to the general rules of the Food Additives Ordinance approved by the Korean Food and Drug Administration It can be judged whether it is suitable or not. The food additives described in the above-mentioned Food Additives Code include chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as persimmon extract, licorice extract, crystalline cellulose, high- A preservative formulation, a tar coloring agent, and the like.
상기 건강기능식품은 골다공증을 포함하는 골 질환 예방 또는 개선을 위한 식품 및 음료 등에 다양하게 이용될 수 있으며, 예컨대, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강기능성 보조 식품, 식품 첨가제 등에 사용될 수 있다.The health functional food may be variously used for foods and beverages for prevention or improvement of osteoporosis including osteoporosis. For example, the health functional food may be used in various foods, beverages, gums, tea, vitamin complex, health functional supplement, .
상기 건강기능식품은 골 질환의 예방 또는 개선을 목적으로, 전체 중량 대비 1.0 내지 10.0 중량%의 치아크레모논을 포함할 수 있다. 상기 치아크레모논의 함량이 1.0 중량% 미만이면 골 질환의 개선 효과가 충분히 구현되지 않을 수 있고 10.0 중량% 초과이면 제품 본연의 품질이 구현되지 않거나 비용 효율이 저하되고 예측되지 아니한 부작용을 유발할 수 있다.The health functional food may contain 1.0 to 10.0% by weight based on the total weight of the composition for the purpose of preventing or improving bone diseases. If the content of dentalclaimone is less than 1.0% by weight, the improvement effect of bone disease may not be sufficiently realized. If the content of dentalclaimone is more than 10.0% by weight, the quality of the product may not be realized or cost efficiency may be deteriorated and unexpected side effects may be caused .
또한, 상기 건강기능식품은 골 질환의 예방 또는 개선을 목적으로 정제, 과립, 분말, 캅셀, 액상의 용액 및 환으로 이루어진 군에서 선택된 어느 하나의 제형으로 제조 및 가공될 수 있다. The health functional food may be prepared and processed into any one form selected from the group consisting of tablets, granules, powders, capsules, liquid solutions and rings for the purpose of preventing or improving bone diseases.
구체적으로 상기 정제 형태의 건강기능식품은 상기 화합물, 부형제, 결합제, 붕해제 및 다른 첨가제와의 혼합물을 통상의 방법으로 과립화한 후, 활택제 등을 넣어 압축 성형하거나, 상기 혼합물을 직접 압축 성형하여 제조할 수 있다. 또한, 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할 수 있으며, 필요에 따라 적당한 제피제로 제피할 수도 있다.Specifically, the health functional food of the tablet form may be prepared by granulating the compound, excipient, binder, disintegrant and other additives in a conventional manner, compression-molding the mixture with a lubricant or the like, . The health functional food of the tablet form may contain a mating agent and the like if necessary, and may be sieved to a suitable skin care agent if necessary.
상기 캅셀 형태의 건강기능식품 중 경질캅셀제는 통상의 경질캅셀에 상기 화합물 및 부형제 등의 첨가제와의 혼합물 또는 그의 입상물 또는 제피한 입상물을 충진하여 제조할 수 있으며, 연질캅셀제는 상기 화합물 및 부형제 등의 첨가제와의 혼합물을 젤라틴 등 캅셀기제에 충진하여 제조할 수 있다. 상기 연질캅셀제는 필요에 따라 글리세린 또는 솔비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다.The hard capsule of the above-mentioned capsule type health functional food can be prepared by filling a normal hard capsule with a mixture of the above compound and an additive such as an excipient, or a granular product thereof or a granular product obtained by soaking the product. And the like can be filled in a capsule base such as gelatin. The soft capsule may contain a plasticizer such as glycerin or sorbitol, a coloring agent, a preservative and the like, if necessary.
상기 환 형태의 건강기능식품은 상기 화합물, 부형제, 결합제, 붕해제 등의 혼합물을 적당한 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 적당한 제피제로 제피를, 또는 전분, 탈크 또는 적당한 물질로 환의를 입힐 수도 있다.The above-mentioned ring-form health functional food can be prepared by molding a mixture of the above compound, excipient, binder, disintegrant and the like by an appropriate method. If necessary, the preparation may be mixed with white sugar or other suitable skin care agent or a starch, talc or a suitable substance It is possible that the
상기 과립형태의 건강기능식품은 상기 화합물, 부형제, 결합제, 붕해제 등의 혼합물을 적당한 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다. The granular health functional food may be prepared by granulating a mixture of the above compound, excipient, binder, disintegrant and the like by a suitable method, and if necessary, may contain a flavoring agent, a mating agent and the like.
또한, 상기 부형제, 결합제, 붕해제, 활택제, 교미제, 착향제 등에 대한 용어 정의는 당업계에 공지된 문헌에 기재된 것으로 그 기능 등이 동일 내지 유사한 것들을 포함할 수 있다. Further, the definitions of the above excipients, binders, disintegrants, lubricants, mating agents, flavoring agents and the like are described in documents known in the art, and the functions and the like may be the same or similar.
이하 실시예를 통해, 본 발명을 더욱 상술하나 하기 실시예에 의해 본 발명이 제한되지 아니함은 자명하다.The present invention will be further described with reference to the following examples, but it should be apparent that the present invention is not limited by the following examples.
실험예Experimental Example 1 : One : 치아크레모논의Teacremo discuss 파골세포에 대한 독성 평가 Toxicity to osteoclasts
파골세포 분화에 있어서 치아크레모논의 잠재적 영향을 평가하고자 마우스 골수 세포 유래의 BMM(bone marrow macrophage)에서 치아크레모논의 파골세포 분화에 대한 세포독성 분석법(cytotoxicity assay)을 수행하였다(도 1A).A cytotoxicity assay for osteoclast differentiation of dental crmomone was performed in BMM (bone marrow macrophage) derived from mouse bone marrow cells in order to evaluate the potential influence of dental crestoma on osteoclast differentiation (Fig. 1A).
MTT assay 결과 치아크레모논은 BMM에서 30 μM의 농도까지 세포독성을 나타내지 않았으며(도 1B), 3일 및 5일 동안 100 ng/mL의 RANKL을 처리한 파골세포 분화 상태에서도 세포독성을 나타내지 않았다(도 1C 및 D).As a result of MTT assay, dicryptone did not show cytotoxicity to the concentration of 30 μM in BMM (FIG. 1B) and did not show cytotoxicity even in the osteoclast differentiation state treated with 100 ng / mL RANKL for 3 and 5 days (Figs. 1C and D).
실험예Experimental Example 2 : 2 : 치아크레모논의Teacremo discuss 파골세포 분화 억제 효과 평가 Evaluation of osteoclast differentiation inhibitory effect
파골세포 분화에 있어서 치아크레모논이 mRNA 발현에 미치는 영향을 분석하였다. 치아크레모논의 처리 유무 및 농도(10 및 30 μM)를 달리하고 BMM을 100 ng/mL의 RANKL에 의해 3일간 분화시켰다.The effect of dental crmmonon on mRNA expression in osteoclast differentiation was analyzed. BMM was differentiated by 100 ng / mL of RANKL for 3 days at different doses and concentrations (10 and 30 μM) of cicammonium treatment.
도 2A 및 2B을 참조하면, 치아크레모논은 RANKL에 의해 유도된 NFATc1 및 c-Fos 유전자의 발현을 하향 조절하였다.Referring to Figures 2A and 2B, dicamycinone down-regulated the expression of RANKL-induced NFATc1 and c-Fos genes.
5일간 RANKL(100ng/mL)에 의한 세포 분화시, TRAP(tartrate-resistant acid phosphatase) assay를 통해 파골세포 형성 정도를 분석하였다.The osteoclast formation was analyzed by TRAP (tartrate-resistant acid phosphatase) assay at 5 days for cell differentiation by RANKL (100 ng / mL).
치아크레모논은 TRAP-양성 스테이닝(TRAP-positive staining)을 억제하였으며(도 2C), 핵(nuclei) 대비 TRAP-양성 다핵 파골세포(MNCs)의 수를 감소시켰다(도 3D). Chiacormonone inhibited TRAP-positive staining (Fig. 2C) and reduced the number of TRAP-positive multinucleated osteoclasts (MNCs) versus nuclei (Fig. 3D).
또한, 파골세포의 골 흡수 기능에 있어서 세포골격 구조의 변화는 필수적이므로, RANKL에 의해 유도된 파골세포 분화 과정에서 F-actin ring formation assay를 수행하였다.In addition, since changes in the cytoskeletal structure of osteoclasts are essential for bone resorption, F-actin ring formation assays were performed in RANKL-induced osteoclast differentiation.
기능적 파골세포 활성을 평가하고자, FITC-phalloidin 및 DAPI로 파골세포를 스테이닝하였다. 현미경을 이용한 면역형광 분석법에 있어서, 치아크레모논은 RANKL에 의한 F-actin의 링 형성을 현저히 억제하였다(도 4C 및 4D). 상기 결과는 치아크레모논이 초기 배양된 마우스 BMM에서 RANKL에 의해 유도된 파골세포 분화를 효과적으로 억제할 수 있음을 시사한다.To evaluate functional osteoclast activity, osteoclasts were stained with FITC-phalloidin and DAPI. In immunofluorescence analysis using a microscope, dia-crmmonon significantly inhibited ring formation of F-actin by RANKL (Fig. 4C and 4D). These results suggest that dicryptone can effectively inhibit RANKL-induced osteoclast differentiation in early-cultured mouse BMM.
실험예Experimental Example 3 : 3: 치아크레모논의Teacremo discuss 조골세포에 대한 독성 평가 Evaluation of toxicity to osteoblast
조골세포 분화에 있어서 치아크레모논의 잠재적 영향을 평가하고자 마우스 두개관 전-조골세포(calvarial pre-osteoblast)에서 세포독성 분석법(cytotoxicity assay)을 수행하였다.Cytotoxicity assays were performed on mouse ovarian calvarial pre-osteoblasts to assess the potential effects of dia- cresomone on osteoblast differentiation.
MTT assay 결과 치아크레모논은 두개관 전-조골세포에 세포 독성을 나타내지 않았으며(도 4A), 5일 동안 골 형성 보충 배지(50 μg/mL의 L- 아스코르빈산 및 10 mM의 베타-글리세롤포스페이트 함유)의 조골세포 분화 상태에서도 세포독성을 나타내지 않았다(도 4B).MTT assay showed that dicryptone did not show cytotoxicity on both osteoblasts (Fig. 4A), and bone formation supplemented medium (50 μg / mL of L-ascorbic acid and 10 mM of beta-glycerol Phosphate) did not show cytotoxicity even in the osteoblast differentiation state (Fig. 4B).
실험예Experimental Example 4 : 4 : 치아크레모논의Teacremo discuss 조골세포 분화 촉진 효과 평가 Evaluation of osteoblast differentiation promoting effect
치아크레모논의 처리 유무 및 농도를 달리하여 치아크레모논이 조골세포 분화에 미치는 영향을 분석하였다.The effect of dental crmmonon on the osteoblast differentiation was analyzed by the presence and concentration of dental crmomon treatment.
조골세포 분화에 대한 치아크레모논의 영향을 분석하고자 초기 조골세포 분화 마커로서 알칼리 포스파타아제 효소 활성(ALP enzymatic activity)을 측정하였다.Alkaline phosphatase activity (ALP enzymatic activity) was measured as an early osteoblast differentiation marker in order to analyze the effect of dia. Cremodone on osteoblast differentiation.
도 5를 참조하면, 치아크레모논은 알칼리 포스파타아제 활성에 영향을 미치지 않았다(도 5A).Referring to FIG. 5, dicamycinone did not affect alkaline phosphatase activity (FIG. 5A).
또한, 후기 조골세포 분화 마커로서 14일 경과 후 ARS 스테이닝을 측정함으로써 석회화 결절 형성(mineralized nodule formation) 정도를 평가하였다.In addition, the degree of mineralized nodule formation was evaluated by measuring ARS staining 14 days later as a late osteoblast differentiation marker.
알칼리 포스파타아제 효소 활성 평과 결과와 마찬가지로, 치아크레모논은 석회화 결절 형성에 영향을 미치지 않았다(도 5B).Similar to the results of alkaline phosphatase enzyme activity, dentalclaimmonon did not affect the formation of calcified nodules (Fig. 5B).
석회화 결절 형성에 대한 정량은 통계적으로 치아크레모논의 조골세포 분화에 대한 효과를 뒷받침하며(도 5C), 상기 결과는 치아크레모논이 조골세포의 분화에 영향을 미치지 아니함을 시사한다.Quantification of calcified nodule formation statistically supports the effect on osteoblast differentiation of dental crestoma (Fig. 5C), suggesting that dental crmmonon does not affect osteoblast differentiation.
본 발명자들은 치아크레모논이 초대 배양된 BMM에서 RANKL에 의해 유도된 파골세포 분화를 저해시키는 반면, 두개관 전-조골세포에서 조골세포의 분화에는 영향을 미치지 아니함을 확인하였다.The present inventors have confirmed that dicryptomone inhibits RANKL-induced osteoclast differentiation in primary cultured BMM, but does not affect osteoblast differentiation in the two osteoblasts.
즉, 치아크레모논은 파골세포발생과 관련된 전사인자 c-Fos 및 NFATc1의 하향 조절을 통해 선택적으로 RANKL에 의해 유도된 파골세포 분화를 저해시켰으나 조골세포의 분화에는 영향을 미치지 아니하였으므로 질병의 증상이나 환자의 특성에 따라 골 질환의 치료의 용도로서 유용하게 활용 가능할 것이다.In other words, dia-crmmonone selectively inhibited osteoclast differentiation induced by RANKL through down-regulation of transcription factors c-Fos and NFATc1, which are associated with osteoclastogenesis, but did not affect osteoblast differentiation, And may be usefully used as a treatment for bone diseases according to characteristics of a patient.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. 예를 들어, 단일형으로 설명되어 있는 각 구성 요소는 분산되어 실시될 수도 있으며, 마찬가지로 분산된 것으로 설명되어 있는 구성 요소들도 결합된 형태로 실시될 수 있다.It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive. For example, each component described as a single entity may be distributed and implemented, and components described as being distributed may also be implemented in a combined form.
본 발명의 범위는 후술하는 특허청구범위에 의하여 나타내어지며, 특허청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.The scope of the present invention is defined by the appended claims, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be construed as being included within the scope of the present invention.
Claims (8)
골다공증, 골형성 부전증, 골연화증, 골량 감소증, 골절, 골 결손 및 고관절 감소증으로 이루어진 군으로부터 하나 이상 선택된 파골세포 분화에 의한 골 질환 예방 또는 치료용 약학적 조성물.
[화학식 1]
A pharmaceutical composition for preventing or treating osteoporosis by osteoclast differentiation selected from the group consisting of osteoporosis, osteogenesis imperfecta, osteomalacia, osteopenia, fracture, bone defect and hip arthropathy.
[Chemical Formula 1]
상기 화학식 1의 화합물은 마늘에서 단리된 파골세포 분화에 의한 골 질환 예방 또는 치료용 약학적 조성물.The method according to claim 1,
The compound of Chemical Formula 1 is a pharmaceutical composition for preventing or treating osteoporosis by osteoclast differentiation isolated from garlic.
RANKL(Receptor activator of NK-κB ligand)에 의해 유도되는 파골세포 분화를 억제하는 파골세포 분화에 의한 골 질환 예방 또는 치료용 약학적 조성물.The method according to claim 1,
A pharmaceutical composition for preventing or treating osteoporosis by osteoclast differentiation inhibiting osteoclast differentiation induced by RANKL (Receptor activator of NK-κB ligand).
조골세포 분화에 영향을 미치지 않는 파골세포 분화에 의한 골 질환 예방 또는 치료용 약학적 조성물.The method according to claim 1,
A pharmaceutical composition for prevention or treatment of osteopathy caused by osteoclast differentiation that does not affect osteoblast differentiation.
인공골, 인공관절, 골 고정재, 골 대체제, 골 수복재, 골 충진재 및 골 이식재로 이루어진 군으로부터 선택된 하나 이상의 물질에 사용되는 파골세포 분화에 의한 골 질환 예방 또는 치료용 약학적 조성물.The method according to claim 1,
A pharmaceutical composition for preventing or treating osteoporosis by osteoclast differentiation used for at least one substance selected from the group consisting of artificial bone, artificial joint, bone fixation agent, bone substitute, bone restoration material, bone filler and bone graft material.
골다공증, 골형성 부전증, 골연화증, 골량 감소증, 골절, 골 결손 및 고관절 감소증으로 이루어진 군으로부터 하나 이상 선택된 파골세포 분화에 의한 골 질환 예방 또는 개선용 건강기능식품.
[화학식 1]
A pharmaceutical composition comprising a compound of the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient,
Osteoporosis, osteogenesis imperfecta, osteomalacia, osteopenia, fracture, bone defect, and hip arthropathy.
[Chemical Formula 1]
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20090035946A (en) * | 2007-10-08 | 2009-04-13 | 충북대학교 산학협력단 | Pharmaceutical composition comprising thiacremonone for preventing or treating cancer |
| KR20110011187A (en) * | 2009-07-28 | 2011-02-08 | 건국대학교 산학협력단 | Pharmaceutical composition for preventing or treating metabolic disease comprising thiacremonone compound as effective component |
| KR20150000663A (en) | 2013-06-25 | 2015-01-05 | 원광대학교산학협력단 | Pharmaceutical Composition for Inhibition of Osteoclast Differentiation |
| KR20160053091A (en) | 2014-10-30 | 2016-05-13 | 순천대학교 산학협력단 | Pharmaceutical composition for prevention or treatment bone diseases comprising Alisma canaliculatum extract or fractions thereof, or compounds isolated from therefrom |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20090035946A (en) * | 2007-10-08 | 2009-04-13 | 충북대학교 산학협력단 | Pharmaceutical composition comprising thiacremonone for preventing or treating cancer |
| KR20110011187A (en) * | 2009-07-28 | 2011-02-08 | 건국대학교 산학협력단 | Pharmaceutical composition for preventing or treating metabolic disease comprising thiacremonone compound as effective component |
| KR20150000663A (en) | 2013-06-25 | 2015-01-05 | 원광대학교산학협력단 | Pharmaceutical Composition for Inhibition of Osteoclast Differentiation |
| KR20160053091A (en) | 2014-10-30 | 2016-05-13 | 순천대학교 산학협력단 | Pharmaceutical composition for prevention or treatment bone diseases comprising Alisma canaliculatum extract or fractions thereof, or compounds isolated from therefrom |
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