Lead Optimization of a Novel Series of Imidazo[1,2-a]pyridine Amides Leading to a Clinical Candidate (Q203) as a Multi- and Extensively-Drug-Resistant Anti-tuberculosis Agent

被引：155

作者：

Kang, Sunhee ^{[1
]}

Kim, Ryang Yeo ^{[2
]}

Seo, Min Jung ^{[1
]}

Lee, Saeyeon ^{[1
]}

Kim, Young Mi ^{[1
]}

Seo, Mooyoung ^{[1
]}

Seo, Jeong Jea ^{[1
]}

Ko, Yoonae ^{[1
]}

Choi, Inhee ^{[1
]}

Jang, Jichan ^{[2
]}

Nam, Jiyoun ^{[3
]}

Park, Seijin ^{[3
]}

Kang, Hwankyu ^{[3
]}

Kim, Hyung Jun ^{[2
]}

Kim, Jungjun ^{[4
]}

Ahn, Sujin ^{[3
]}

Pethe, Kevin ^{[2
]}

Nam, Kiyean ^{[4
]}

No, Zaesung ^{[1
]}

Kim, Jaeseung ^{[1
]}

机构：

[1] Inst Pasteur Korea, Med & Bioorgan Chem Grp, Songnam 463400, Gyeonggi Do, South Korea

[2] Inst Pasteur Korea, Antibacterial Drug Discovery Grp, Songnam 463400, Gyeonggi Do, South Korea

[3] Inst Pasteur Korea, Drug Metab & Pharmacokinet Grp, Songnam 463400, Gyeonggi Do, South Korea

[4] Qurient Inc, Songnam 463400, Gyeonggi Do, South Korea

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 12期

基金：

新加坡国家研究基金会;

关键词：

TUBERCULOSIS;

D O I：

10.1021/jm5003606

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A critical unmet clinical need to combat the global tuberculosis epidemic is the development of potent agents capable of reducing the time of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis therapy. In this paper, we report on the optimization of imidazo[1,2-a]pyridine amide (IPA) lead compound 1, which led to the design and synthesis of Q203 (50). We found that the amide linker with IPA core is very important for activity against Mycobacterium tuberculosis H37Rv. Linearity and lipophilicity of the amine part in the IPA series play a critical role in improving in vitro and in vivo efficacy and pharmacokinetic profile. The optimized IPAs 49 and 50 showed not only excellent oral bioavailability (80.2% and 90.7%, respectively) with high exposure of the area under curve (AUC) but also displayed significant colony-forming unit (CFU) reduction (1.52 and 3.13 log(10) reduction at 10 mg/kg dosing level, respectively) in mouse lung.

引用

页码：5293 / 5305

页数：13

共 17 条

[1] Identification of Novel Imidazo[1,2-a]pyridine Inhibitors Targeting M. tuberculosis QcrB [J].

Abrahams, Katherine A. ;

Cox, Jonathan A. G. ;

Spivey, Vickey L. ;

Loman, Nicholas J. ;

Pallen, Mark J. ;

Constantinidou, Chrystala ;

Fernandez, Raquel ;

Alemparte, Carlos ;

Remuinan, Modesto J. ;

Barros, David ;

Ballell, Lluis ;

Besra, Gurdyal S. .

PLOS ONE, 2012, 7 (12)

[2] A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis [J].

Andries, K ;

Verhasselt, P ;

Guillemont, J ;

Göhlmann, HWH ;

Neefs, JM ;

Winkler, H ;

Van Gestel, J ;

Timmerman, P ;

Zhu, M ;

Lee, E ;

Williams, P ;

de Chaffoy, D ;

Huitric, E ;

Hoffner, S ;

Cambau, E ;

Truffot-Pernot, C ;

Lounis, N ;

Jarlier, V .

SCIENCE, 2005, 307 (5707) :223-227

[3]

[Anonymous], 2012, GLOBAL TUBERCULOSIS

[4] High Content Screening Identifies Decaprenyl-Phosphoribose 2′ Epimerase as a Target for Intracellular Antimycobacterial Inhibitors [J].

Christophe, Thierry ;

Jackson, Mary ;

Jeon, Hee Kyoung ;

Fenistein, Denis ;

Contreras-Dominguez, Monica ;

Kim, Jaeseung ;

Genovesio, Auguste ;

Carralot, Jean-Philippe ;

Ewann, Fanny ;

Kim, Eun Hye ;

Lee, Sae Yeon ;

Kang, Sunhee ;

Seo, Min Jung ;

Park, Eun Jung ;

Skovierova, Henrieta ;

Pham, Ha ;

Riccardi, Giovanna ;

Nam, Ji Youn ;

Marsollier, Laurent ;

Kempf, Marie ;

Joly-Guillou, Marie-Laure ;

Oh, Taegwon ;

Shin, Won Kyung ;

No, Zaesung ;

Nehrbass, Ulf ;

Brosch, Roland ;

Cole, Stewart T. ;

Brodin, Priscille .

PLOS PATHOGENS, 2009, 5 (10)

[5] Randomized Pilot Trial of Eight Weeks of Bedaquiline (TMC207) Treatment for Multidrug-Resistant Tuberculosis: Long-Term Outcome, Tolerability, and Effect on Emergence of Drug Resistance [J].

Diacon, A. H. ;

Donald, P. R. ;

Pym, A. ;

Grobusch, M. ;

Patientia, R. F. ;

Mahanyele, R. ;

Bantubani, N. ;

Narasimooloo, R. ;

De Marez, T. ;

van Heeswijk, R. ;

Lounis, N. ;

Meyvisch, P. ;

Andries, K. ;

McNeeley, D. F. .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2012, 56 (06) :3271-3276

[6] Early Bactericidal Activity and Pharmacokinetics of PA-824 in Smear-Positive Tuberculosis Patients [J].

Diacon, Andreas H. ;

Dawson, Rodney ;

Hanekom, Madeleine ;

Narunsky, Kim ;

Maritz, Stefan J. ;

Venter, Amour ;

Donald, Peter R. ;

van Niekerk, Christo ;

Whitney, Karl ;

Rouse, Doris J. ;

Laurenzi, Martino W. ;

Ginsberg, Ann M. ;

Spigelman, Melvin K. .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2010, 54 (08) :3402-3407

[7]

Gler MT, 2012, NEW ENGL J MED, V366, P2151, DOI 10.1056/NEJMoa1112433

[8] A High-Throughput Screen To Identify Inhibitors of ATP Homeostasis in Non-replicating Mycobacterium tuberculosis [J].

Mak, Puiying A. ;

Rao, Srinivasa P. S. ;

Tan, Mai Ping ;

Lin, Xiuhua ;

Chyba, Jason ;

Tay, Joann ;

Ng, Seow Hwee ;

Tan, Bee Huat ;

Cherian, Joseph ;

Duraiswamy, Jeyaraj ;

Bifani, Pablo ;

Lim, Vivian ;

Lee, Boon Heng ;

Ma, Ngai Ling ;

Beer, David ;

Thayalan, Pamela ;

Kuhen, Kelli ;

Chatterjee, Arnab ;

Supek, Frantisek ;

Glynne, Richard ;

Zheng, Jun ;

Boshoff, Helena I. ;

Barry, Clifton E., III ;

Dick, Thomas ;

Pethe, Kevin ;

Camacho, Luis R. .

ACS CHEMICAL BIOLOGY, 2012, 7 (07) :1190-1197

[9] Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis [J].

Makarov, Vadim ;

Manina, Giulia ;

Mikusova, Katarina ;

Moellmann, Ute ;

Ryabova, Olga ;

Saint-Joanis, Brigitte ;

Dhar, Neeraj ;

Pasca, Maria Rosalia ;

Buroni, Silvia ;

Lucarelli, Anna Paola ;

Milano, Anna ;

De Rossi, Edda ;

Belanova, Martina ;

Bobovska, Adela ;

Dianiskova, Petronela ;

Kordulakova, Jana ;

Sala, Claudia ;

Fullam, Elizabeth ;

Schneider, Patricia ;

McKinney, John D. ;

Brodin, Priscille ;

Christophe, Thierry ;

Waddell, Simon ;

Butcher, Philip ;

Albrethsen, Jakob ;

Rosenkrands, Ida ;

Brosch, Roland ;

Nandi, Vrinda ;

Bharath, Sowmya ;

Gaonkar, Sheshagiri ;

Shandil, Radha K. ;

Balasubramanian, Venkataraman ;

Balganesh, Tanjore ;

Tyagi, Sandeep ;

Grosset, Jacques ;

Riccardi, Giovanna ;

Cole, Stewart T. .

SCIENCE, 2009, 324 (5928) :801-804

[10] Design, synthesis and structure - activity relationship of novel RXR-selective modulators [J].

Michellys, PY ;

D'Arrigo, J ;

Grese, TA ;

Karanewsky, DS ;

Leibowitz, MD ;

Mais, DA ;

Mapes, CM ;

Reifel-Miller, A ;

Rungta, D ;

Boehm, MF .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (06) :1593-1598

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