Discovery and optimization of novel 3-piperazinylcoumarin antagonist of chemokine-like factor 1 with oral antiasthma activity in mice.
Chemokine-like factor 1 (CKLF1) is a novel functional cytokine that acts through its receptor CC chemokine receptor 4 (CCR4). Activation of CCR4 by CKLF1 plays an important role in diseases such as asthma and multiple sclerosis. This article describes a cell-based screening assay using an FITC-labeled CCR4 agonist (CKLF1-C27), a CKLF1 peptide fragment. Screening of our in-stock small-molecule library identified a 3-piperazinylcoumarin analogue 1 (IC(50) = 4.36 x 10(-6) M) that led to the discovery of orally active compound 41 (IC(50) = 2.12 x 10(-8) M) through systematic optimization. Compound 41 blocked the calcium mobilization and chemotaxis induced by CKLF1-C27 and reduced the asthmatic pathologic changes in lung tissue of human CKLF1-transfected mice. Further studies indicated that compound 41 ameliorated pathological changes via inhibition of the NF-kappaB signal pathway.
Li
Gang
G
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 2 Nanwei Rd, Beijing 100050, PR China.
Wang
Dongmei
D
Sun
Mingna
M
Li
Guangyan
G
Hu
Jinfeng
J
Zhang
Yun
Y
Yuan
Yuhe
Y
Ji
Haijie
H
Chen
Naihong
N
Liu
Gang
G
D000284:Administration, Oral; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D018925:Chemokines / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D002633:Chemotaxis / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005355:Fibrosis; D057166:High-Throughput Screening Assays; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D062792:MARVEL Domain-Containing Proteins; D051379:Mice; D016328:NF-kappa B / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D054398:Receptors, CCR4 / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D013329:Structure-Activity Relationship
C547954:5,7-dihydroxy-4-methyl-3-(4-methylpiperazin-1-yl)-2H-chromen-2-one; D018927:Anti-Asthmatic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; C515354:CCR4 protein, human; C432676:CKLF protein, human; D018925:Chemokines; D003374:Coumarins; D062792:MARVEL Domain-Containing Proteins; D016328:NF-kappa B; D010446:Peptide Fragments; D010879:Piperazines; D054398:Receptors, CCR4; D002118:Calcium