发现四氢吡唑并嘧啶甲酰胺衍生物作为强效口服活性抗结核药物。
Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents.
作者信息
Yokokawa Fumiaki, Wang Gang, Chan Wai Ling, Ang Shi Hua, Wong Josephine, Ma Ida, Rao Srinivasa P S, Manjunatha Ujjini, Lakshminarayana Suresh B, Herve Maxime, Kounde Cyrille, Tan Bee Huat, Thayalan Pamela, Ng Seow Hwee, Nanjundappa Mahesh, Ravindran Sindhu, Gee Peck, Tan Maria, Wei Liu, Goh Anne, Chen Pei-Yu, Lee Kok Sin, Zhong Chen, Wagner Trixie, Dix Ina, Chatterjee Arnab K, Pethe Kevin, Kuhen Kelli, Glynne Richard, Smith Paul, Bifani Pablo, Jiricek Jan
机构信息
Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
出版信息
ACS Med Chem Lett. 2013 Apr 1;4(5):451-5. doi: 10.1021/ml400071a. eCollection 2013 May 9.
Abstract
Tetrahydropyrazolo[1,5-a]pyrimidine scaffold was identified as a hit series from a Mycobacterium tuberculosis (Mtb) whole cell high through-put screening (HTS) campaign. A series of derivatives of this class were synthesized to evaluate their structure-activity relationship (SAR) and structure-property relationship (SPR). Compound 9 had a promising in vivo DMPK profile in mouse and exhibited potent in vivo activity in a mouse efficacy model, achieving a reduction of 3.5 log CFU of Mtb after oral administration to infected mice once a day at 100 mg/kg for 28 days. Thus, compound 9 is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB.
摘要
四氢吡唑并[1,5-a]嘧啶骨架是在结核分枝杆菌（Mtb）全细胞高通量筛选（HTS）活动中鉴定出的一个有活性的系列。合成了该类别的一系列衍生物，以评估它们的构效关系（SAR）和构性关系（SPR）。化合物9在小鼠体内具有良好的药物代谢动力学特征，并在小鼠疗效模型中表现出强大的体内活性，以100mg/kg的剂量每天口服给药感染小鼠28天，可使Mtb的CFU减少3.5个对数。因此，化合物9是用于敏感和耐药结核病联合治疗的潜在候选药物。
相似文献
1
Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents.发现四氢吡唑并嘧啶甲酰胺衍生物作为强效口服活性抗结核药物。
ACS Med Chem Lett. 2013 Apr 1;4(5):451-5. doi: 10.1021/ml400071a. eCollection 2013 May 9.
2
Identification of a novel inhibitor of isocitrate lyase as a potent antitubercular agent against both active and non-replicating Mycobacterium tuberculosis.鉴定一种新型异柠檬酸裂解酶抑制剂作为针对活性和非复制性结核分枝杆菌的强效抗结核药物。
Tuberculosis (Edinb). 2016 Mar;97:38-46. doi: 10.1016/j.tube.2015.12.003. Epub 2016 Jan 6.
3
Design, synthesis, and bioevaluation of a novel class of (E)-4-oxo-crotonamide derivatives as potent antituberculosis agents.设计、合成及新型（E）-4-氧代-巴豆酰胺衍生物类化合物作为潜在抗结核药物的生物评价。
Bioorg Med Chem Lett. 2019 Feb 15;29(4):539-543. doi: 10.1016/j.bmcl.2019.01.001. Epub 2019 Jan 3.
4
Discovery of the disubstituted oxazole analogues as a novel class anti-tuberculotic agents against MDR- and XDR-MTB.发现二取代恶唑类似物作为一类新型抗耐多药和广泛耐药结核分枝杆菌的抗结核药物。
Bioorg Med Chem Lett. 2015 Nov 15;25(22):5178-81. doi: 10.1016/j.bmcl.2015.09.072. Epub 2015 Oct 1.
5
Synthesis of new generation triazolyl- and isoxazolyl-containing 6-nitro-2,3-dihydroimidazooxazoles as anti-TB agents: in vitro, structure-activity relationship, pharmacokinetics and in vivo evaluation.新一代含三唑基和异恶唑基的6-硝基-2,3-二氢咪唑并恶唑类抗结核药物的合成：体外研究、构效关系、药代动力学及体内评价
Org Biomol Chem. 2015 Mar 28;13(12):3610-24. doi: 10.1039/c5ob00054h.
6
Synthesis, Structure-Activity Relationship, and Mechanistic Studies of Aminoquinazolinones Displaying Antimycobacterial Activity.具有抗分枝杆菌活性的氨基喹唑啉酮的合成、构效关系及作用机制研究
ACS Infect Dis. 2020 Jul 10;6(7):1951-1964. doi: 10.1021/acsinfecdis.0c00252. Epub 2020 Jun 15.
7
Novel and potent calcium-sensing receptor antagonists: discovery of (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide monotosylate (TAK-075) as an orally active bone anabolic agent.新型强效钙敏感受体拮抗剂的发现：（5R）-N-[1-乙基-1-(4-乙基苯基)丙基]-2,7,7-三甲基-5-苯基-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺单对甲苯磺酸盐（TAK-075）作为一种口服活性骨合成代谢剂。
Bioorg Med Chem. 2011 Mar 15;19(6):1881-94. doi: 10.1016/j.bmc.2011.02.001. Epub 2011 Feb 24.
8
Design, Synthesis, and Biological Evaluation of Pyrazolo[1,5-a]pyridine-3-carboxamides as Novel Antitubercular Agents.吡唑并[1,5-a]吡啶-3-甲酰胺作为新型抗结核药物的设计、合成及生物学评价
ACS Med Chem Lett. 2015 Jun 11;6(7):814-8. doi: 10.1021/acsmedchemlett.5b00176. eCollection 2015 Jul 9.
9
Design, synthesis and investigation on the structure-activity relationships of N-substituted 2-aminothiazole derivatives as antitubercular agents.N-取代2-氨基噻唑衍生物作为抗结核药物的设计、合成及构效关系研究
Eur J Med Chem. 2014 Jan 24;72:26-34. doi: 10.1016/j.ejmech.2013.11.007. Epub 2013 Nov 13.
10
Design, synthesis, and biological evaluation of novel 4H-chromen-4-one derivatives as antituberculosis agents against multidrug-resistant tuberculosis.新型 4H-色烯-4-酮衍生物的设计、合成及作为抗多重耐药结核分枝杆菌的抗结核药物的生物评价。
Eur J Med Chem. 2020 Mar 1;189:112075. doi: 10.1016/j.ejmech.2020.112075. Epub 2020 Jan 19.
引用本文的文献
1
New pyrazole-based derivatives targeting MmpL3 transporter in Mycobacterium tuberculosis: design, synthesis, biological evaluation and molecular docking studies.新型靶向结核分枝杆菌MmpL3转运蛋白的吡唑基衍生物：设计、合成、生物学评价及分子对接研究
Mol Divers. 2025 Mar 14. doi: 10.1007/s11030-025-11152-3.
2
NMR-Verified Dearomatization of 5,7-Substituted Pyrazolo[1,5-a]pyrimidines.5,7-取代吡唑并[1,5-a]嘧啶的核磁共振验证脱芳构化反应
Molecules. 2023 Sep 12;28(18):6584. doi: 10.3390/molecules28186584.
3
Highly enantioselective Rh-catalyzed asymmetric reductive dearomatization of multi-nitrogen polycyclic pyrazolo[1,5-]pyrimidines.铑催化多氮多环吡唑并[1,5 - ]嘧啶的高度对映选择性不对称还原脱芳构化反应
Chem Sci. 2023 Jul 28;14(34):9048-9054. doi: 10.1039/d3sc02086j. eCollection 2023 Aug 30.
4
Prevalence of CYP2C9 and CYP2C19 variants and the impact on clopidogrel efficacy in patients having CYPC19*2 variant.CYP2C9 和 CYP2C19 变异体的流行率以及 CYP2C19*2 变异体患者中对氯吡格雷疗效的影响。
Indian J Pharmacol. 2023 Jan-Feb;55(1):27-33. doi: 10.4103/ijp.ijp_706_22.
5
Tuberculosis Drug Discovery: A Decade of Hit Assessment for Defined Targets.结核病药物发现：针对明确靶点的十年评估。
Front Cell Infect Microbiol. 2021 Mar 15;11:611304. doi: 10.3389/fcimb.2021.611304. eCollection 2021.
6
Molecule Property Analyses of Active Compounds for .针对. 的活性化合物的分子性质分析
J Med Chem. 2020 Sep 10;63(17):8917-8955. doi: 10.1021/acs.jmedchem.9b02075. Epub 2020 Apr 20.
7
Direct Inhibition of MmpL3 by Novel Antitubercular Compounds.新型抗结核化合物对MmpL3的直接抑制作用。
ACS Infect Dis. 2019 Jun 14;5(6):1001-1012. doi: 10.1021/acsinfecdis.9b00048. Epub 2019 Mar 28.
8
MmpL3 as a Target for the Treatment of Drug-Resistant Nontuberculous Mycobacterial Infections.MmpL3作为治疗耐多药非结核分枝杆菌感染的靶点
Front Microbiol. 2018 Jul 10;9:1547. doi: 10.3389/fmicb.2018.01547. eCollection 2018.
9
Drug discovery for the developing world: progress at the Novartis Institute for Tropical Diseases.面向发展中世界的药物研发：诺华热带病研究所的进展
Nat Rev Drug Discov. 2015 Jun;14(6):442-4. doi: 10.1038/nrd4001-c1.
10
The tuberculosis drug discovery and development pipeline and emerging drug targets.结核病药物发现与开发流程及新出现的药物靶点
Cold Spring Harb Perspect Med. 2015 Jan 29;5(6):a021154. doi: 10.1101/cshperspect.a021154.
本文引用的文献
1
Fueling open-source drug discovery: 177 small-molecule leads against tuberculosis.推动开源药物研发：177 个针对结核病的小分子先导化合物。
ChemMedChem. 2013 Feb;8(2):313-21. doi: 10.1002/cmdc.201200428. Epub 2013 Jan 10.
2
Novel and potent calcium-sensing receptor antagonists: discovery of (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide monotosylate (TAK-075) as an orally active bone anabolic agent.新型强效钙敏感受体拮抗剂的发现：（5R）-N-[1-乙基-1-(4-乙基苯基)丙基]-2,7,7-三甲基-5-苯基-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺单对甲苯磺酸盐（TAK-075）作为一种口服活性骨合成代谢剂。
Bioorg Med Chem. 2011 Mar 15;19(6):1881-94. doi: 10.1016/j.bmc.2011.02.001. Epub 2011 Feb 24.
3
Discovery of novel and potent orally active calcium-sensing receptor antagonists that stimulate pulselike parathyroid hormone secretion: synthesis and structure-activity relationships of tetrahydropyrazolopyrimidine derivatives.发现新型强效口服钙敏感受体拮抗剂，刺激脉冲样甲状旁腺激素分泌：四氢吡唑并嘧啶衍生物的合成及构效关系。
J Med Chem. 2011 Mar 10;54(5):1430-40. doi: 10.1021/jm101452x. Epub 2011 Feb 9.
4
The challenge of new drug discovery for tuberculosis.结核病新药研发面临的挑战。
Nature. 2011 Jan 27;469(7331):483-90. doi: 10.1038/nature09657.
5
Synthesis and structure-activity relationship of tetrahydropyrazolopyrimidine derivatives--a novel structural class of potent calcium-sensing receptor antagonists.四氢吡唑并嘧啶衍生物的合成及构效关系--一种新型强效钙敏感受体拮抗剂。
Bioorg Med Chem. 2010 Dec 15;18(24):8501-11. doi: 10.1016/j.bmc.2010.10.035. Epub 2010 Oct 20.
6
A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy.结核分枝杆菌的化学遗传学筛选鉴定出无体内疗效的碳源依赖性生长抑制剂。
Nat Commun. 2010 Aug 24;1(5):57. doi: 10.1038/ncomms1060.
7
Global tuberculosis drug development pipeline: the need and the reality.全球结核病药物研发管线：需求与现实。
Lancet. 2010 Jun 12;375(9731):2100-9. doi: 10.1016/S0140-6736(10)60359-9. Epub 2010 May 18.
8
Antituberculosis activity of the molecular libraries screening center network library.分子库筛选中心网络库的抗结核活性。
Tuberculosis (Edinb). 2009 Sep;89(5):354-63. doi: 10.1016/j.tube.2009.07.006. Epub 2009 Sep 26.
9
Liquid-phase synthesis of combinatorial libraries based on 7-trifluoromethyl-substituted pyrazolo[1,5-a]pyrimidine scaffold.基于7-三氟甲基取代的吡唑并[1,5-a]嘧啶支架的组合库的液相合成。
J Comb Chem. 2005 Mar-Apr;7(2):236-45. doi: 10.1021/cc049855o.
Zotero 插件