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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027361 | PMC |
| http://dx.doi.org/10.1021/ml400071a | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents.
ACS Med Chem Lett
May 2013
Novartis Institute for Tropical Diseases, 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
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.
View Article and Find Full Text PDFIdentification, synthesis, and biological evaluation of 6-[(6R)-2-(4-fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one (AS1940477), a potent p38 MAP kinase inhibitor.
J Med Chem
September 2012
Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
Several p38 MAPK inhibitors have been shown to effectively block the production of cytokines such as IL-1β, TNFα, and IL-6. Inhibitors of p38 MAP kinase therefore have significant therapeutic potential for the treatment of autoimmune disease. Compound 2a was identified as a potent TNFα production inhibitor in vitro but suffered from poor oral bioavailability.
View Article and Find Full Text PDFNovel 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.
Bioorg Med Chem
March 2011
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 2-17-85, Jusohomachi, Yodogawa-ku, Osaka 532-8686, Japan.
The calcium-sensing receptor antagonist (CaSR) has been recognized as a promising target of anabolic agents for treating osteoporosis. In the course of developing a new drug candidate for osteoporosis, we found tetrahydropyrazolopyrimidine derivative 1 to be an orally active CaSR antagonist that stimulated transient PTH secretion in rats. However, compound 1 showed poor physical and chemical stability.
View Article and Find Full Text PDFDiscovery of novel and potent orally active calcium-sensing receptor antagonists that stimulate pulselike parathyroid hormone secretion: synthesis and structure-activity relationships of tetrahydropyrazolopyrimidine derivatives.
J Med Chem
March 2011
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85 Jusohonmachi-2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
As part of our research for novel calcium-sensing receptor (CaSR) antagonists that can function as oral bone anabolic agents, we recently reported the discovery of a tetrahydropyrazolopyrimidine derivative featuring adamantyl group 1b with potent CaSR antagonistic activity. To explore the potential of this calcilytic congener, we introduced the gem-dialkyl benzyl group at the 3-position of the tetrahydropyrazolopyrimidine ring, forming a bioisostere of the adamantyl group by mimicking the adamantyl group's lipophilicity and bulkiness. Optimization directed toward the improvement of solubility and metabolic stability led to the discovery of compound 9e, which stimulated transient PTH secretion when orally administered to normal rats.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!