- Development of Pyrazolopyrimidine Anti- Wolbachia Agents for the Treatment of Filariasis
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Anti-Wolbachia therapy has been identified as a viable treatment for combating filarial diseases. Phenotypic screening revealed a series of pyrazolopyrimidine hits with potent anti-Wolbachia activity. This paper focuses on the exploration of the SAR for this chemotype, with improvement of metabolic stability and solubility profiles using medicinal chemistry approaches. Organic synthesis has enabled functionalization of the pyrazolopyrimidine core at multiple positions, generating a library of compounds of which many analogues possess nanomolar activity against Wolbachia in vitro with improved DMPK parameters. A lead compound, 15f, was selected for in vivo pharmacokinetics (PK) profiling in mice. The combination of potent anti-Wolbachia activity in two in vitro assessments plus the exceptional oral PK profiles in mice puts this lead compound in a strong position for in vivo proof-of-concept pharmacodynamics studies and demonstrates the strong potential for further optimization and development of this series for treatment of filariasis in the future.
- Berry, Neil G.,Cassidy, Andrew,Clare, Rachel H.,Cook, Darren A.,Ford, Louise,Hong, W. David,Johnston, Kelly L.,Kavanagh, Stefan,Leung, Suet C.,McGillan, Paul,Nixon, Gemma L.,O'Neill, Paul M.,Taylor, Mark J.,Ward, Stephen A.,Webborn, Peter J. H.,Wenlock, Mark C.
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supporting information
p. 1421 - 1426
(2021/09/11)
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- Preparation and application of novel quinolizine pH fluorescence molecular probe
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The invention discloses a novel quinolizine pH fluorescence molecular probe which has brand-new action mechanism as shown in the specification, wherein a skeleton structure is 4H-quinolizine-4-imine as shown in the compound in the formula II, C-N bond in
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Paragraph 0018; 0022
(2018/04/03)
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- Pyrazolotriazines as inhibitors of nucleases
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The invention provides compounds represented by the structural formula (1): wherein R1, R2, R3 and R4 are as defined in the claims. The compounds are inhibitors of nucleases, and are useful in particular in a method of treatment and/or prevention of proliferative diseases, neurodegenerative diseases, and other genomic instability associated diseases.
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Paragraph 0045; 0046; 0047; 0048; 0055-0059
(2016/01/12)
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- Discovery and characterization of a novel 7-aminopyrazolo[1,5-a]pyrimidine analog as a potent hepatitis C virus inhibitor
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We describe a novel 7-aminopyrazolo[1,5-a]pyrimidine (7-APP) derivative as a potent hepatitis C virus (HCV) inhibitor. A series of 7-APPs was synthesized and evaluated for inhibitory activity against HCV in different cell culture systems. The synthesis and preliminary structure-activity relationship study of 7-APP are reported.
- Hwang, Jong Yeon,Windisch, Marc Peter,Jo, Suyeon,Kim, Keumhyun,Kong, Sunju,Kim, Hyoung Cheul,Kim, Soohyun,Kim, Heeyoung,Lee, Myung Eun,Kim, Youngmi,Choi, Jihyun,Park, Dong-Sik,Park, Eunjung,Kwon, Jeongjin,Nam, Jiyoun,Ahn, Sujin,Cechetto, Jonathan,Kim, Junwon,Liuzzi, Michel,No, Zaesung,Lee, Jinhwa
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p. 7297 - 7301
(2013/02/23)
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- Benzodiazepine receptor ligands III. Synthesis and biological evaluation of 2- and/or 3-substituted pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides
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A new series of 2- and/or 3-substituted pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides and their 8-chloro derivatives were synthesized, and their benzodiazepine receptor (BZR) affinities were evaluated in vitro in comparison to lead compound 3-ethoxycarbonyl-8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide (29) [1,2]. None of the new compounds showed significant affinity for BZR. On the basis of a pharmacophore/receptor model suggested for lead compound 29, some hypotheses to explain the inactivity of new derivatives are discussed.
- Guerrini,Costanzo,Bruni,Ciciani,Selleri,Gratteri,Costa,Martini,Lucacchini
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p. 375 - 389
(2007/10/03)
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