Discovery of the Development Candidate N-tert-Butyl Nodulisporamide: A Safe and Efficacious Once Monthly Oral Agent for the Control of Fleas and Ticks on Companion Animals
Discovery of the Development Candidate N-tert-Butyl Nodulisporamide: A Safe and Efficacious Once Monthly Oral Agent for the Control of Fleas and Ticks on Companion Animals
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DOI：
10.1021/jm801334v
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发表时间：
2009-06-11
影响因子：
7.3
通讯作者：
Shoop, Wesley L.
中科院分区：
文献类型：
--
作者：
Meinke, Peter T.;Colletti, Steven L.;Shoop, Wesley L.
节孢酸A（1）是一种结构复杂的真菌代谢物，通过调节无脊椎动物特异性谷氨酸门控离子通道对跳蚤表现出全身性疗效。为了鉴定适合犬每月经口给药的节孢菌酰胺，在人工跳蚤饲养系统中检查了335种节孢菌酰胺库的内在全身效价，并在小鼠/臭虫试验中检查了全身有效性和安全性。选择66种节孢酰胺的队列在犬/跳蚤模型中进行评价;药代动力学分析将血浆水平与跳蚤疗效相关。这些努力导致开发候选物N-叔丁基nodulisporamide（3）被鉴定为每月一次的强效和有效的口服药物，用于控制犬和猫身上的跳蚤和蜱虫，并与局部药物氟虫腈和吡虫啉进行了直接比较，获得了有利的结果。超过3个月的多次给药研究证实了体内杀外寄生虫的功效，并确定3没有明显的哺乳动物毒性。使用[C-14]-标记的3在小鼠中进行的组织分布研究表明，脂肪床作为配体储库，有助于这些化合物的长终末半衰期。
Nodulisporic acid A (1) is a structurally complex fungal metabolite that exhibits systemic efficacy against fleas via modulation of an invertebrate specific glutamate-gated ion channel. In order to identify a nodulisporamide suitable for monthly oral dosing in dogs, a library of 335 nodulisporamides was examined in an artificial flea feeding system for intrinsic systemic potency as well as in a mouse/bedbug assay for systemic efficacy and safety. A cohort of 66 nodulisporamides were selected for evaluation in a dog/flea model; pharmacokinetic analysis correlated plasma levels with flea efficacy. These efforts resulted in the identification of the development candidate N-tert-butyl nodulisporamide (3) as a potent and efficacious once monthly oral agent for the control of fleas and ticks on dogs and cats which was directly compared to the topical agents fipronil and imidacloprid, with favorable results obtained. Multidose studies over 3 months confirmed the in vivo ectoparasiticidal efficacy and established that 3 lacked overt mammalian toxicity. Tissue distribution studies in mice using [C-14]-labeled 3 indicate that adipose beds serve as ligand depots, contributing to the long terminal half-lives of these compounds.