Discovery of Tetrahydropyrazolopyrimidine Carboxamide Derivatives As Potent and Orally Active Antitubercular Agents
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- 作者：Fumiaki Yokokawa ; Gang Wang ; Wai Ling Chan ; Shi Hua Ang ; Josephine Wong ; Ida Ma ; Srinivasa P S Rao ; Ujjini Manjunatha ; Suresh B Lakshminarayana ; Maxime Herve ; Cyrille Kounde ; Bee Huat Tan ; Pamela Thayalan ; Seow Hwee Ng ; Mahesh Nanjundappa ; Sindhu Ravindran ; Peck Gee ; Maria Tan ; Liu Wei ; Anne Goh ; Pei-Yu Chen ; Kok Sin Lee ; Chen Zhong ; Trixie Wagner ; Ina Dix ; Arnab K. Chatterjee ; Kevin Pethe ; Kelli Kuhen ; Richard Glynne ; Paul Smith ; Pablo Bifani ; Jan Jiricek
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：May 9, 2013
- 年：2013
- 卷：4
- 期：5
- 页码：451-455
- 全文大小：266K
- 年卷期：v.4,no.5(May 9, 2013)
- ISSN：1948-5875
文摘
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鈥揳ctivity relationship (SAR) and structure鈥損roperty 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.