- Design, synthesis and biological evaluation of novel benzothiadiazine derivatives as potent PI3Kδ-selective inhibitors for treating B-cell-mediated malignancies
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A series of 24 benzothiadiazine derivatives with structural novelty were designed, synthesized and biologically evaluated as PI3Kδ-selective inhibitors. As a consequence of the structure-activity relationship (SAR) study, compounds 63 and 71 were identifi
- Ma, Xiaodong,Wei, Jun,Wang, Chang,Gu, Dongyan,Hu, Yongzhou,Sheng, Rong
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p. 112 - 125
(2019/03/17)
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- Discovery of Conformationally Restricted Human Glutaminyl Cyclase Inhibitors as Potent Anti-Alzheimer's Agents by Structure-Based Design
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Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disease whose pathogenesis cannot be defined by one single element but consists of various factors; thus, there is a call for alternative approaches to tackle the multifaceted aspects of AD. Among the potential alternative targets, we aim to focus on glutaminyl cyclase (QC), which reduces the toxic pyroform of β-amyloid in the brains of AD patients. On the basis of a putative active conformation of the prototype inhibitor 1, a series of N-substituted thiourea, urea, and α-substituted amide derivatives were developed. The structure-activity relationship analyses indicated that conformationally restrained inhibitors demonstrated much improved QC inhibition in vitro compared to nonrestricted analogues, and several selected compounds demonstrated desirable therapeutic activity in an AD mouse model. The conformational analysis of a representative inhibitor indicated that the inhibitor appeared to maintain the Z-E conformation at the active site, as it is critical for its potent activity.
- Hoang, Van-Hai,Ngo, Van T.H.,Cui, Minghua,Manh, Nguyen Van,Tran, Phuong-Thao,Ann, Jihyae,Ha, Hee-Jin,Kim, Hee,Choi, Kwanghyun,Kim, Young-Ho,Chang, Hyerim,MacAlino, Stephani Joy Y.,Lee, Jiyoun,Choi, Sun
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supporting information
p. 8011 - 8027
(2019/10/11)
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- Discovery of HTL6641, a dual orexin receptor antagonist with differentiated pharmacodynamic properties
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A novel series of potent, selective, and orally efficacious dual antagonists of the orexin receptors has been investigated, resulting in the identification of lead compound 27 (HTL6641). Comprehensive data for 27 are presented, including in vivo PK parame
- Christopher, John A.,Aves, Sarah J.,Brown, Jason,Errey, James C.,Klair, Suki S.,Langmead, Christopher J.,Mace, Oliver J.,Mould, Richard,Patel, Jayesh C.,Tehan, Benjamin G.,Zhukov, Andrei,Marshall, Fiona H.,Congreve, Miles
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supporting information
p. 947 - 955
(2015/05/27)
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- OREXIN RECEPTOR ANTAGONISTS
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The disclosures herein relate to novel compounds of formula wherein W, X and Y1, Y2, Y3 and Y4 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of neurological or psychiatric disorders associated with orexin receptors.
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Page/Page column 71
(2014/01/18)
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