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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 저널정보
- 한국약제학회 Journal of Pharmaceutical Investigation Journal of Pharmaceutical Investigation 제48권 제5호
- 발행연도
- 2018.9
- 수록면
- 585 - 593 (9page)
- DOI
- 10.1007/s40005-017-0352-6
이용수
초록· 키워드
오류제보하기
The ultimate goal of this study was to identify an orally active, affordable, potent and safe antimalarial drug based on the natural product artemisinin. During these efforts, a series of novel 7β-hydroxyartemisinin analogs were synthesized and characterized in vitro for their antimalarial activity against Plasmodium falciparum. Heterodimerization of 7β-hydroxyartemisinin provided the asymmetrical carbamate (ARB-89) while homodimerization provided the carbonate (ARB-92). These dimers were found to be highly active in vitro with an IC50 ≤ 0.50 nM against P. falciparum infected human red blood cells (RBC). For further development as potential antimalarial agents, a battery of in vitro and in vivo pharmacokinetic experiments was performed to distinguish the fate of the discovery compounds ARB-89 and ARB-92. Two UPLC-MS methods were developed and validated for the analysis of the compounds. Both ARB- 89 and ARB-92 exhibited moderate affinity (51 and 56%, respectively) to parasitized RBC, which is a perquisite for antimalarial activity. Following a single dose oral and intravenous pharmacokinetic study in rats, ARB-89 displayed a high clearance (92.8 ± 5.6 L/h kg), short elimination half-life ( t1/2, 1.2 ± 0.2 h) and moderate oral bioavailability (23.4%). ARB-89 was found to be excreted unchanged in feces, which may be due to its high lipophilicity, molecular weight and low oral exposure. In an attempt to identify a better lead antimalarial compound, ARB-92 was designed to be more water soluble than ARB-89 by incorporating a protonatable tertiary amine as part of the dimerizing ligand for 7β-hydroxyartemisinin. As anticipated, ARB-92 displayed a lower clearance (2.9 ± 0.7 L/h kg) and subsequently a longer t1/ 2 (2.3 ± 0.2 h) compared to ARB-89. The oral bioavailability of ARB-92 was found to be 34% in rats, a value somewhat better than the marketed artemisinin derivatives artenimol (19.3%), artemether (19.7%) or artesunate (29.5%).
목차
등록된 정보가 없습니다.
참고문헌 (25)
참고문헌 신청
Ackerman BH / 1988 / Vancomycin serum protein binding determination by ultrafiltration / Drug Intell Clin Pharm 22:300~303
Asawamahasakda W / 1994 / The interaction of artemisinin with red cell membranes / J Lab Clin Med 123:757~762
Avery MA / 2009 / Development and testing of new antimalarial drugs, CDC-Cooperative agreement 5 U01 C100211-03 / Department of Medicinal Chemistry, The University of Mississippi
Avery MA / 1999 / Synthesis and structure-activity relationships of peroxidic antimalarials based on artemisinin;Advances in medicinal chemistry / Elsevier :125~217
Davies B / 1993 / Physiological parameters in laboratory animals and humans / Pharm Res 10:1093~1095
Asawamahasakda W / 1994 / The interaction of artemisinin with red cell membranes / J Lab Clin Med 123:757~762
Avery MA / 2009 / Development and testing of new antimalarial drugs, CDC-Cooperative agreement 5 U01 C100211-03 / Department of Medicinal Chemistry, The University of Mississippi
Avery MA / 1999 / Synthesis and structure-activity relationships of peroxidic antimalarials based on artemisinin;Advances in medicinal chemistry / Elsevier :125~217
Davies B / 1993 / Physiological parameters in laboratory animals and humans / Pharm Res 10:1093~1095
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