CCR5 receptor antagonists: Discovery and SAR of novel 4-hydroxypiperidine derivatives
Optimizing the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde, which is a hit from high-throughput screening (HTS), let to discover the potent 4-hydroxypiperidine derivatives as a CCR5 receptor antagonist. The guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde, 1, with an IC...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2007-04, Vol.17 (7), p.1883-1887 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Lu, Shou-Fu Chen, Binglong Davey, Dave Dunning, Laura Jaroch, Stefan May, Karen Onuffer, James Phillips, Gary Subramanyam, Babu Tseng, Jih-Lie Wei, Robert G. Wei, Ming Ye, Bin |
| description | Optimizing the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde, which is a hit from high-throughput screening (HTS), let to discover the potent 4-hydroxypiperidine derivatives as a CCR5 receptor antagonist.
The guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde,
1, with an IC
50 of 840
nM against the CCR5 receptor was identified using high-throughput screening. Optimization efforts led to the discovery of a novel piperidine series of CCR5 antagonists. In particular, the 4-hydroxypiperidine derivative,
6k, had improved potency against CCR5, and was a starting point for further optimization. SAR elaboration using parallel synthesis led to the identification of
10h, a potent CCR5 antagonist with an IC
50 of 11
nM. |
| doi_str_mv | 10.1016/j.bmcl.2007.01.050 |
| format | Article |
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The guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde,
1, with an IC
50 of 840
nM against the CCR5 receptor was identified using high-throughput screening. Optimization efforts led to the discovery of a novel piperidine series of CCR5 antagonists. In particular, the 4-hydroxypiperidine derivative,
6k, had improved potency against CCR5, and was a starting point for further optimization. SAR elaboration using parallel synthesis led to the identification of
10h, a potent CCR5 antagonist with an IC
50 of 11
nM.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2007.01.050</identifier><identifier>PMID: 17314043</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Animals ; Biological and medical sciences ; CCR5 Receptor Antagonists ; Cell Line ; Chemistry, Pharmaceutical - methods ; Chemokine ; Drug Design ; Humans ; Hydroxypiperidine ; Inhibitory Concentration 50 ; Medical sciences ; Miscellaneous ; Models, Chemical ; Molecular Conformation ; Molecular Structure ; Pharmacology. Drug treatments ; Piperidines - chemical synthesis ; Piperidines - chemistry ; Piperidines - pharmacology ; Rats ; Structure-Activity Relationship ; Time Factors ; Transfection</subject><ispartof>Bioorganic & medicinal chemistry letters, 2007-04, Vol.17 (7), p.1883-1887</ispartof><rights>2007 Elsevier Ltd</rights><rights>2007 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-8844e917222730ff020f2dc1d4f8da7135019c43d5c67e8024a31ec369a017ea3</citedby><cites>FETCH-LOGICAL-c415t-8844e917222730ff020f2dc1d4f8da7135019c43d5c67e8024a31ec369a017ea3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X07001023$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18632115$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17314043$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lu, Shou-Fu</creatorcontrib><creatorcontrib>Chen, Binglong</creatorcontrib><creatorcontrib>Davey, Dave</creatorcontrib><creatorcontrib>Dunning, Laura</creatorcontrib><creatorcontrib>Jaroch, Stefan</creatorcontrib><creatorcontrib>May, Karen</creatorcontrib><creatorcontrib>Onuffer, James</creatorcontrib><creatorcontrib>Phillips, Gary</creatorcontrib><creatorcontrib>Subramanyam, Babu</creatorcontrib><creatorcontrib>Tseng, Jih-Lie</creatorcontrib><creatorcontrib>Wei, Robert G.</creatorcontrib><creatorcontrib>Wei, Ming</creatorcontrib><creatorcontrib>Ye, Bin</creatorcontrib><title>CCR5 receptor antagonists: Discovery and SAR of novel 4-hydroxypiperidine derivatives</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Optimizing the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde, which is a hit from high-throughput screening (HTS), let to discover the potent 4-hydroxypiperidine derivatives as a CCR5 receptor antagonist.
The guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde,
1, with an IC
50 of 840
nM against the CCR5 receptor was identified using high-throughput screening. Optimization efforts led to the discovery of a novel piperidine series of CCR5 antagonists. In particular, the 4-hydroxypiperidine derivative,
6k, had improved potency against CCR5, and was a starting point for further optimization. SAR elaboration using parallel synthesis led to the identification of
10h, a potent CCR5 antagonist with an IC
50 of 11
nM.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>CCR5 Receptor Antagonists</subject><subject>Cell Line</subject><subject>Chemistry, Pharmaceutical - methods</subject><subject>Chemokine</subject><subject>Drug Design</subject><subject>Humans</subject><subject>Hydroxypiperidine</subject><subject>Inhibitory Concentration 50</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Models, Chemical</subject><subject>Molecular Conformation</subject><subject>Molecular Structure</subject><subject>Pharmacology. 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The guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde,
1, with an IC
50 of 840
nM against the CCR5 receptor was identified using high-throughput screening. Optimization efforts led to the discovery of a novel piperidine series of CCR5 antagonists. In particular, the 4-hydroxypiperidine derivative,
6k, had improved potency against CCR5, and was a starting point for further optimization. SAR elaboration using parallel synthesis led to the identification of
10h, a potent CCR5 antagonist with an IC
50 of 11
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| ispartof | Bioorganic & medicinal chemistry letters, 2007-04, Vol.17 (7), p.1883-1887 |
| issn | 0960-894X 1464-3405 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Biological and medical sciences CCR5 Receptor Antagonists Cell Line Chemistry, Pharmaceutical - methods Chemokine Drug Design Humans Hydroxypiperidine Inhibitory Concentration 50 Medical sciences Miscellaneous Models, Chemical Molecular Conformation Molecular Structure Pharmacology. Drug treatments Piperidines - chemical synthesis Piperidines - chemistry Piperidines - pharmacology Rats Structure-Activity Relationship Time Factors Transfection |
| title | CCR5 receptor antagonists: Discovery and SAR of novel 4-hydroxypiperidine derivatives |
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