다발성 경화증 (multiple sclerosis, MS)은 뇌 및 척수의 신경 세포의 수초(myelin)가 손상되며 발상하는 염증성 질환이다. 핀고리모드 (Fingolimod)는 Novartis가 S1P1 agonist로 개발한 의약품으로, 재발성 MS의 치료제로 승인된 최초의 경구 투여 치료제이다. 생체 내에서 인산화된 후, 활성 형태인 핀고리모드 ...
다발성 경화증 (multiple sclerosis, MS)은 뇌 및 척수의 신경 세포의 수초(myelin)가 손상되며 발상하는 염증성 질환이다. 핀고리모드 (Fingolimod)는 Novartis가 S1P1 agonist로 개발한 의약품으로, 재발성 MS의 치료제로 승인된 최초의 경구 투여 치료제이다. 생체 내에서 인산화된 후, 활성 형태인 핀고리모드 인산염은 5 개의 S1P 수용체 중 4 개 (S1P1, S1P3, S1P4, S1P5)에 결합 친화성을 갖는다. 특히 S1P3 수용체에 대한 높은 결합 친화력은 서맥 (bradycardia)이라는 부작용을 일으킨다. 따라서 S1P1 수용체에 선택적 효능을 갖는 치료제의 개발이 필요하다. S1P1 수용체에 선택적 효능을 갖는 MS의 치료제를 개발하기 위하여 다양한 방면으로 연구하던 중, 우리나라 제주도 해양 천연물로부터 S1P1에 대해 높은 활성 (EC50 = 8.2 μM)을 나타내는 화합물 (E)-8-oxooctadec-9-enoic acid (W-137-6F5E)을 발견하였다. 추가적인 연구 및 in vivo assay가 필요하였으나 해양 천연물로부터의 추출법으로는 시료량의 확보에 한계가 있어 화학적인 합성법으로 합성하고자 하였다. 합성을 위해 retrosynthesis로 합성법을 고안하였고 출발물질을 suberic acid로 하여 6 단계 반응으로 합성법을 개발하였고, 7.2%의 수득률로 (E)-8-oxooctadec-9-enoic acid을 얻었다. 합성한 (E)-8-oxooctadec-9-enoic acid는 천연물과의 1H NMR 비교를 통하여 천연물로부터 추출된 W-137-6F5E 화합물과 동일한 구조임을 확인하였다. 또한 enone을 기본 골격으로 하는 유도체를 합성하였다. 첫 번째로 enone의 양 옆에 방향성 벤젠 고리를 도입하고, 두 번째로 오른쪽 말단의 polar head 그룹은 carboxylic acid와 amino carboxylic acid로 치환시켜 구조변화에 따른 활성 효과를 평가 하였다. 6 ~ 8 단계에 걸쳐 유도체 6 개를 합성하였고 화합물들의 S1P1에 대한 in vitro 활성을 평가하였는데 그 결과 KKJE0507 화합물이 S1P1 assay (10 μM)에서 높은 저해 활성을 보였고, 각각 95.11% (Ca2+ assay), 73.72% (β-arrestin assay), 91.08% (internalization assay)로 높은 활성을 보였다. Ca2+ assay에서 EC50는 0.61 μM이었다.
주제어: 다발성 경화증, S1P 수용체, S1P, 선택적 작용제
다발성 경화증 (multiple sclerosis, MS)은 뇌 및 척수의 신경 세포의 수초(myelin)가 손상되며 발상하는 염증성 질환이다. 핀고리모드 (Fingolimod)는 Novartis가 S1P1 agonist로 개발한 의약품으로, 재발성 MS의 치료제로 승인된 최초의 경구 투여 치료제이다. 생체 내에서 인산화된 후, 활성 형태인 핀고리모드 인산염은 5 개의 S1P 수용체 중 4 개 (S1P1, S1P3, S1P4, S1P5)에 결합 친화성을 갖는다. 특히 S1P3 수용체에 대한 높은 결합 친화력은 서맥 (bradycardia)이라는 부작용을 일으킨다. 따라서 S1P1 수용체에 선택적 효능을 갖는 치료제의 개발이 필요하다. S1P1 수용체에 선택적 효능을 갖는 MS의 치료제를 개발하기 위하여 다양한 방면으로 연구하던 중, 우리나라 제주도 해양 천연물로부터 S1P1에 대해 높은 활성 (EC50 = 8.2 μM)을 나타내는 화합물 (E)-8-oxooctadec-9-enoic acid (W-137-6F5E)을 발견하였다. 추가적인 연구 및 in vivo assay가 필요하였으나 해양 천연물로부터의 추출법으로는 시료량의 확보에 한계가 있어 화학적인 합성법으로 합성하고자 하였다. 합성을 위해 retrosynthesis로 합성법을 고안하였고 출발물질을 suberic acid로 하여 6 단계 반응으로 합성법을 개발하였고, 7.2%의 수득률로 (E)-8-oxooctadec-9-enoic acid을 얻었다. 합성한 (E)-8-oxooctadec-9-enoic acid는 천연물과의 1H NMR 비교를 통하여 천연물로부터 추출된 W-137-6F5E 화합물과 동일한 구조임을 확인하였다. 또한 enone을 기본 골격으로 하는 유도체를 합성하였다. 첫 번째로 enone의 양 옆에 방향성 벤젠 고리를 도입하고, 두 번째로 오른쪽 말단의 polar head 그룹은 carboxylic acid와 amino carboxylic acid로 치환시켜 구조변화에 따른 활성 효과를 평가 하였다. 6 ~ 8 단계에 걸쳐 유도체 6 개를 합성하였고 화합물들의 S1P1에 대한 in vitro 활성을 평가하였는데 그 결과 KKJE0507 화합물이 S1P1 assay (10 μM)에서 높은 저해 활성을 보였고, 각각 95.11% (Ca2+ assay), 73.72% (β-arrestin assay), 91.08% (internalization assay)로 높은 활성을 보였다. Ca2+ assay에서 EC50는 0.61 μM이었다.
Multiple sclerosis is an inflammatory disease that is thought to impair the insulated cover of neurons in the brain and spinal cord. The Fingolimod, developed by Novartis as an S1P1 agonist, is the first oral treatment approved for the treatment of MS. After phosphorylation in vivo, the active form,...
Multiple sclerosis is an inflammatory disease that is thought to impair the insulated cover of neurons in the brain and spinal cord. The Fingolimod, developed by Novartis as an S1P1 agonist, is the first oral treatment approved for the treatment of MS. After phosphorylation in vivo, the active form, the Fingolimod phosphate, has binding affinity to four of the five S1P receptors (S1P1, S1P3, S1P4, and S1P5). In particular, the high binding affinity to S1PR3 causes side effects of bradycardia. Therefore, it is necessary to develop new drugs with selective efficacy for S1P1. Therefore, the development strategy of the new drug for the treatment of multiple sclerosis lowers lymphocyte migration to the central nervous system through internalization of S1P1 receptor, promotes regeneration of several seconds by the regulation of S1P5 receptor, and does not bind S1P3 receptor. In order to develop a therapeutic agent for MS that targets S1P1 receptor and S1P5 receptor according to the strategy described above, it was found that a compound having high activity against S1P1 (EC50 = 8.2 μM) among the compounds extracted from marine natural products in Jeju Island ((E) -8-oxooctadec-9-enoic acid (W-137-6F5E)). Additional complementary studies and in vivo efficacy studies were needed, but the method of extraction from marine natural products was limited to obtaining the amount of sample. Therefore we have synthesized by chemical synthetic method. For synthesis, we have retrosynthetic analysis, and synthetic strategy was designed including Wittig reaction as a key step starts from suberic acid. A total of 6 steps of the reaction is 7.2% yield. The synthesized (E) -8-oxooctadec-9-enoic acid was confirmed to have the same structure as the W-137-6F5E compound extracted from the natural product through 1H NMR comparison with the natural product. In addition, a derivative having enone as a basic skeleton was synthesized. Especially, firstly aromatic benzene rings were introduced on both sides of the enone, and secondly, polar head group at the right end was substituted with carboxylic acid and amino carboxylic acid. Six compounds were synthesized in 6 ~ 8 steps. In vitro activity of the compounds against S1P1 was evaluated. As a result, KKJE0507 showed high inhibitory activity in S1P1 assay (10 μM) and 95.11% (Ca2+ assay), 73.72% (β–arrestin assay) and 91.08% (internalization assay), respectively. The EC50 in the Ca2+ assay was 0.61 μM.
Multiple sclerosis is an inflammatory disease that is thought to impair the insulated cover of neurons in the brain and spinal cord. The Fingolimod, developed by Novartis as an S1P1 agonist, is the first oral treatment approved for the treatment of MS. After phosphorylation in vivo, the active form, the Fingolimod phosphate, has binding affinity to four of the five S1P receptors (S1P1, S1P3, S1P4, and S1P5). In particular, the high binding affinity to S1PR3 causes side effects of bradycardia. Therefore, it is necessary to develop new drugs with selective efficacy for S1P1. Therefore, the development strategy of the new drug for the treatment of multiple sclerosis lowers lymphocyte migration to the central nervous system through internalization of S1P1 receptor, promotes regeneration of several seconds by the regulation of S1P5 receptor, and does not bind S1P3 receptor. In order to develop a therapeutic agent for MS that targets S1P1 receptor and S1P5 receptor according to the strategy described above, it was found that a compound having high activity against S1P1 (EC50 = 8.2 μM) among the compounds extracted from marine natural products in Jeju Island ((E) -8-oxooctadec-9-enoic acid (W-137-6F5E)). Additional complementary studies and in vivo efficacy studies were needed, but the method of extraction from marine natural products was limited to obtaining the amount of sample. Therefore we have synthesized by chemical synthetic method. For synthesis, we have retrosynthetic analysis, and synthetic strategy was designed including Wittig reaction as a key step starts from suberic acid. A total of 6 steps of the reaction is 7.2% yield. The synthesized (E) -8-oxooctadec-9-enoic acid was confirmed to have the same structure as the W-137-6F5E compound extracted from the natural product through 1H NMR comparison with the natural product. In addition, a derivative having enone as a basic skeleton was synthesized. Especially, firstly aromatic benzene rings were introduced on both sides of the enone, and secondly, polar head group at the right end was substituted with carboxylic acid and amino carboxylic acid. Six compounds were synthesized in 6 ~ 8 steps. In vitro activity of the compounds against S1P1 was evaluated. As a result, KKJE0507 showed high inhibitory activity in S1P1 assay (10 μM) and 95.11% (Ca2+ assay), 73.72% (β–arrestin assay) and 91.08% (internalization assay), respectively. The EC50 in the Ca2+ assay was 0.61 μM.
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