- Quinoline-4-carboxamide skeleton derivative and application thereof
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The invention discloses a quinoline-4-formamide skeleton derivative and application thereof, belonging to the field of chemical medicines. The invention provides a compound as shown in a formula I or pharmaceutically acceptable salt thereof. The invention
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Paragraph 0048-0051; 0080-0083
(2021/06/09)
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- Discovery of Potent Small-Molecule SIRT6 Activators: Structure-Activity Relationship and Anti-Pancreatic Ductal Adenocarcinoma Activity
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SIRT6 activation is thought to be a promising target for the treatment of many diseases, particularly cancer. Herein, we report the discovery of a series of new small-molecule SIRT6 activators. Structure-activity relationship analyses led to the identific
- Chen, Xiuli,Sun, Weining,Huang, Shenzhen,Zhang, Hailin,Lin, Guifeng,Li, Hui,Qiao, Jingxin,Li, Linli,Yang, Shengyong
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p. 10474 - 10495
(2020/11/02)
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- Discovering novel chemical inhibitors of human cyclophilin A: Virtual screening, synthesis, and bioassay
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Cyclophilin A (CypA) is a member of cyclophilins, a family of the highly homologous peptidyl prolyl cis-trans isomerases (PPIases), which can bind to cyclosporin A (CsA). CypA plays critical roles in various biological processes, including protein folding, assembly, transportation, regulation of neuron growth, and HIV replication. The discovery of CypA inhibitor is now of a great special interest in the treatment of immunological disorders. In this study, a series of novel small molecular CypA inhibitors have been discovered by using structure-based virtual screening in conjunction with chemical synthesis and bioassay. The SPECS_1 database containing 85,000 small molecular compounds was searched by virtual screening against the crystal structure of human CypA. After SPR-based binding affinity assay, 15 compounds were found to show binding affinities to CypA at submicro-molar or micro-molar level (compounds 1-15). Seven compounds were selected as the starting point for the further structure modification in considering binding activity, synthesis difficulty, and structure similarity. We thus synthesized 40 new small molecular compounds (1-6, 15, 16a-q, 17a-d, and 18a-l), and four of which (compounds 16b, 16h, 16k, and 18g) showed high CypA PPIase inhibition activities with IC50s of 2.5-6.2 μM. Pharmacological assay indicated that these four compounds demonstrated somewhat inhibition activities against the proliferation of spleen cells.
- Li, Jian,Chen, Jing,Gui, Chunshan,Zhang, Li,Qin, Yu,Xu, Qiang,Zhang, Jian,Liu, Hong,Shen, Xu,Jiang, Hualiang
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p. 2209 - 2224
(2007/10/03)
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- Discovery of a novel class of selective non-peptide antagonists for the human neurokinin-3 receptor. 1. Identification of the 4-quinolinecarboxamide framework
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A novel class of potent and selective non-peptide neurokinin-3 (NK-3) receptor antagonists, featuring the 4-quinolinecarboxamide framework, has been designed based upon chemically diverse NK-1 receptor antagonists. The novel compounds 33-76, prompted by chemical modifications of the prototype 4, have been characterized by binding analysis using a membrane preparation of chinese hamster ovary (CHO) cells expressing the human neurokinin-3 receptors (hNK-3-CHO), and clear structure-activity relationships (SARs) have been established. From SARs, (R)-N-[α-(methoxycarbonyl)benzyl]-2- phenylquinoline-4-carboxamide (65, SB 218795, hNK-3-CHO binding K(i) = 13 nM) emerged as one of the most potent compounds of this novel class. Selectivity studies versus the other neurokinin receptors (hNK-2-CHO and hNK-1-CHO) revealed that 65 is about 90-fold selective for hNK-3 versus hNK-2 receptors (hNK-2-CHO binding K(i) = 1221 nM) and over 7000-fold selective versus hNK-1 receptors (hNK-1-CHO binding K(i) = >100 μM). In vitro functional studies in rabbit isolated iris sphincter muscle preparation demonstrated that 65 is a competitive antagonist of the contractile response induced by the potent and selective NK-3 receptor agonist senktide with a K(b) = 43 nM. Overall, the data indicate that 65 is a potent and selective hNK-3 receptor antagonist and a useful lead for further chemical optimization.
- Giardina, Giuseppe A. M.,Sarau, Henry M.,Farina, Carlo,Medhurst, Andrew D.,Grugni, Mario,Raveglia, Luca F.,Schmidt, Dulcie B.,Rigolio, Roberto,Luttmann, Mark,Vecchietti, Vittorio,Hay, Douglas W. P.
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p. 1794 - 1807
(2007/10/03)
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