- Discovery of bioavailable 4,4-disubstituted piperidines as potent ligands of the chemokine receptor 5 and inhibitors of the human immunodeficiency virus-1
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We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the 125I-[MIP-1β] binding and Ba-L-HOS antiviral assays resulted in the discovery of 64 and 68 in the 4,4-disubstitited piperidine class H, both potent CCR5 ligands (pIC50 = 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC50 = 7.80 and 7.84, respectively, in Ba-L-HOS assay). In addition, 64 and 68 were bioavailable in rodents, establishing them as lead molecules for further optimization toward CCR5 clinical candidates.
- Kazmierski, Wieslaw M.,Aquino, Christopher,Chauder, Brian A.,Deanda, Felix,Ferris, Robert,Jones-Hertzog, Deborah K.,Kenakin, Terrence,Koble, Cecilia S.,Watson, Christian,Wheelan, Pat,Yang, Hanbiao,Youngman, Michael
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p. 6538 - 6546
(2009/11/30)
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- High affinity, selective neurokinin 2 and neurokinin 3 receptor antagonists from a common structural template
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High affinity, selective hNK2 or hNK3 ligands can be prepared from the common template 1 in a few simple chemical operations. The hNK3 ligands 3 antagonise the calcium mobilisation caused by activation of hNK3 receptors expressed in CHO cells as measured using fura-2 microspectrofluorimetry.
- Harrison,Korsgaard,Swain,Cascieri,Sadowski,Seabrook
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p. 1343 - 1348
(2007/10/03)
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- A practical and scalable synthesis of SR 142801, a tachykinin NK3 antagonist
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A practical and scalable total synthesis of tachykinin NK3 receptor antagonist SR 142801, (R)-N-[1-[3-[1-benzoyl-3-(3,4-dichlorophenyl)-3-piperidinyl]propyl]-4-phenyl-4 -piperidinyl]-N-methyl acetamide 1 is described. The absolute configuration of the key intermediate 7 was determined by single crystal X-ray crystallography, on the basis of which, the absolute configuration of SR 142801 should be (R)-(+), instead of the recently reported (S)-(+).
- Chen, Huai G.,Chung,Goel,Johnson,Kesten,Knobelsdorf,Lee,Rubin
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p. 555 - 560
(2007/10/03)
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