Novel Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Anti-malarial Activity in the Mouse Model

被引：112

作者：

Booker, Michael L. ^{[1
]}

Bastos, Cecilia M. ^{[1
]}

Kramer, Martin L. ^{[1
]}

Barker, Robert H., Jr. ^{[1
]}

Skerlj, Renato ^{[1
]}

Sidhu, Amar Bir ^{[2
]}

Deng, Xiaoyi ^{[9
]}

Celatka, Cassandra ^{[1
]}

Cortese, Joseph F. ^{[2
]}

Bravo, Jose E. Guerrero ^{[3
]}

Llado, Keila N. Crespo ^{[3
]}

Serrano, Adelfa E. ^{[3
]}

Angulo-Barturen, Inigo ^{[4
]}

Belen Jimenez-Diaz, Maria ^{[4
]}

Viera, Sara ^{[4
]}

Garuti, Helen ^{[4
]}

Wittlin, Sergio ^{[5
,6
]}

Papastogiannidis, Petros ^{[5
,6
]}

Lin, Jing-wen ^{[7
]}

Janse, Chris J. ^{[7
]}

Khan, Shahid M. ^{[7
]}

Duraisingh, Manoj ^{[8
]}

Coleman, Bradley ^{[8
]}

Goldsmith, Elizabeth J. ^{[10
]}

Phillips, Margaret A. ^{[9
]}

Munoz, Benito ^{[2
]}

Wirth, Dyann F. ^{[8
]}

Klinger, Jeffrey D. ^{[1
]}

Wiegand, Roger ^{[2
]}

Sybertz, Edmund ^{[1
]}

机构：

[1] Genzyme Corp, Waltham, MA 02451 USA

[2] Harvard & MIT, Broad Inst, Cambridge, MA 02141 USA

[3] Univ Puerto Rico, Sch Med, Dept Microbiol & Med Zool, San Juan, PR 00936 USA

[4] GlaxoSmithKline, Dis Developing World, Tres Cantos 28760, Spain

[5] Swiss Trop & Publ Hlth Inst, CH-4002 Basel, Switzerland

[6] Univ Basel, CH-4003 Basel, Switzerland

[7] Leiden Univ, Med Ctr, Ctr Infect Dis, Leiden Malaria Res Grp,Dept Parasitol, NL-2333 ZA Leiden, Netherlands

[8] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA

[9] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA

[10] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2010年 / 285卷 / 43期

基金：

美国国家卫生研究院;

关键词：

HIGH-EFFICIENCY TRANSFECTION; IN-VITRO; SACCHAROMYCES-CEREVISIAE; PYRIMIDINE PATHWAY; ESCHERICHIA-COLI; RODENT MALARIA; ENZYMES; BERGHEI; BIOSYNTHESIS; IDENTIFICATION;

D O I：

10.1074/jbc.M110.162081

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1-yl) thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH from P. falciparum, P. vivax, and P. berghei. The compounds were selective for the parasite enzymes over human DHODH, and x-ray structural data on the analog Genz-667348, demonstrated that species selectivity could be attributed to amino acid differences in the inhibitor-binding site. Compounds from this series demonstrated in vitro potency against the 3D7 and Dd2 strains of P. falciparum, good tolerability and oral exposure in the mouse, and ED50 values in the 4-day murine P. berghei efficacy model of 13-21 mg/kg/day with oral twice-daily dosing. In particular, treatment with Genz-667348 at 100 mg/kg/day resulted in sterile cure. Two recent analogs of Genz-667348 are currently undergoing pilot toxicity testing to determine suitability as clinical development candidates.

引用

页码：33054 / 33064

页数：11

共 56 条

[1] A Murine Model of falciparum-Malaria by In Vivo Selection of Competent Strains in Non-Myelodepleted Mice Engrafted with Human Erythrocytes [J].