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Discovery of Tetrahydropyrazolopyrimidine Carboxamide De-rivatives as Potent and Orally Active Novel Anti-Tubercular Agents

Yokokawa, Fumiaki and Wang, Gang and Wong, Josephine and Rao, Srinivasa P.S. and Manjunatha, Ujjini Havaldar and Lakshminarayana, Suresh Bangalore and Herve, Maxime Marcel and Kounde, Cyrille Stephane and Tan, Bee Huat and Thayalan, Pamela and Ng, Seow Hwee and Nanjundappa, Mahesh Bangalore and Zhang, Chengzhi and Wagner, Beatrix and Dix, Ina and Kuhen, Kelli and Glynne, Richard and Smith, Paul William and Bifani, Juan Pablo and Jiricek, Jan and Seah, Peck Gee and Liu, Wei and Chen, Pei-Yu and Lee, Kok Sin and Chan, Wai Ling and Ma, Ida and Chatterjee, Arnab and Pethe, Kevin and Tan, Maria and Goh, Anne and Ang, Shi-Hua and Seah, Peck Gee (2013) Discovery of Tetrahydropyrazolopyrimidine Carboxamide De-rivatives as Potent and Orally Active Novel Anti-Tubercular Agents. ACS Medicinal Chemistry Letters, 4 (5). pp. 451-455. ISSN 1948-5875

Abstract

ABSTRACT: Tetrahydropyrazolopyrimidine 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 showed potent bactericidal effect and activity against multi-drug resistant tuberculosis (MDR TB) strains. Furthermore 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 the compound 9 is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB.

Item Type: Article
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/9563

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