Macrofilaricidal Benzimidazole-Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness: Part 1. Amide Linked Analogs

被引：9

作者：

Akama, Tsutomu ^{[1
]}

Freund, Yvonne R. ^{[1
]}

Berry, Pamela W. ^{[1
]}

Carter, David S. ^{[1
]}

Easom, Eric E. ^{[1
]}

Jarnagin, Kurt ^{[1
]}

Lunde, Christopher S. ^{[1
]}

Plattner, Jacob J. ^{[1
]}

Rock, Fernando ^{[1
]}

Stefanakis, Rianna ^{[1
]}

Fischer, Chelsea ^{[2
]}

Bulman, Christina A. ^{[2
]}

Lim, Kee Chong ^{[2
]}

Suzuki, Brian M. ^{[3
]}

Tricoche, Nancy ^{[4
]}

Mansour, Abdelmoneim ^{[5
]}

DiCosty, Utami ^{[5
]}

McCall, Scott ^{[5
]}

Carson, Ben ^{[5
]}

McCall, John W. ^{[5
]}

McKerrow, James ^{[3
]}

Huebner, Marc P. ^{[6
]}

Specht, Sabine ^{[6
,7
]}

Hoerauf, Achim ^{[6
]}

Lustigman, Sara ^{[4
]}

Sakanari, Judy A. ^{[2
]}

Jacobs, Robert T. ^{[1
]}

机构：

[1] Anacor Pharmaceut Inc, Palo Alto, CA 94303 USA

[2] Univ Calif San Francisco, San Francisco, CA 94143 USA

[3] Univ Calif San Diego, La Jolla, CA 92093 USA

[4] New York Blood Ctr, New York, NY 10021 USA

[5] TRS Labs Inc, Athens, GA USA

[6] Univ Hosp Bonn, Bonn, Germany

[7] Drugs Neglected Dis Initiat, Geneva, Switzerland

来源：

ACS INFECTIOUS DISEASES | 2020年 / 6卷 / 02期

关键词：

onchocerciasis; lymphatic filariasis; flubendazole; tubulin; organoboron; ANTHELMINTIC DRUG FLUBENDAZOLE; MULTIDRUG-RESISTANCE; IN-VITRO; POTENTIAL TREATMENT; RAT EMBRYOS; IVERMECTIN; MODEL; PHARMACOKINETICS; IDENTIFICATION; DISCOVERY;

D O I：

10.1021/acsinfecdis.9b00396

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of benzimidazole benzoxaborole hybrid molecules linked via an amide linker are described that exhibit good in vitro activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as river blindness. The lead identified in this series, 8a (AN8799), was found to have acceptable pharmacokinetic properties to enable evaluation in animal models of human filariasis. Compound 8a was effective in killing Brugia malayi, B. pahangi, and Litomosoides sigmodontis worms present in Mongolian gerbils when dosed subcutaneously as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 28 days. The measurement of plasma levels of 8a at the end of the dosing period and at the time of sacrifice revealed an interesting dependence of activity on the extended exposure for both 8a and the positive control, flubendazole.

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页码：173 / +

页数：13

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