Discovery of Bioavailable 4,4-Disubstituted Piperidines as Potent Ligands of the Chemokine Receptor 5 and Inhibitors of the Human Immunodeficiency Virus-1

被引：32

作者：

Kazmierski, Wieslaw M. ^{[1
]}

Aquino, Christopher ^{[6
]}

Chauder, Brian A. ^{[6
]}

Deanda, Felix ^{[3
]}

Ferris, Robert ^{[1
]}

Jones-Hertzog, Deborah K. ^{[4
]}

Kenakin, Terrence ^{[2
]}

Koble, Cecilia S. ^{[6
]}

Watson, Christian ^{[2
]}

Wheelan, Pat ^{[5
]}

Yang, Hanbiao

Youngman, Michael ^{[1
]}

机构：

[1] GlaxoSmithKline Inc, Infect Dis Ctr Excellence Drug Discovery, Res Triangle Pk, NC 27709 USA

[2] GlaxoSmithKline Inc, Mol Discovery Res, Res Triangle Pk, NC 27709 USA

[3] GlaxoSmithKline Inc, Computat & Struct Chem, Res Triangle Pk, NC 27709 USA

[4] GlaxoSmithKline Inc, Drug Discovery IT, Res Triangle Pk, NC 27709 USA

[5] GlaxoSmithKline Inc, ID DMPK, Res Triangle Pk, NC 27709 USA

[6] GlaxoSmithKline Inc, Metab Pathways Ctr Excellence Drug Discovery, Res Triangle Pk, NC 27709 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 20期

关键词：

D O I：

10.1021/jm800598a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the (125)I-[MIP-1 beta] 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 (pIC(50) = 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC(50) = 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.

引用

页码：6538 / 6546

页数：9

共 31 条

[11] Development of a high-throughput viral-free assay for the measurement of CCR5-mediated HIV/cell fusion
Jenkinson, S
McCoy, D
Kerner, S
Ferris, R
Lawrence, W
Fox, T
Smith, C
[J]. RECEPTORS & CHANNELS, 2003, 9 (02) : 117 - 123
[12] Recent progress in discovery of small-molecule CCR5 chemokine receptor ligands as HIV-1 inhibitors (vol 11, pg 2663, 2003)
Kazmierski, W
Bifulco, N
Yang, HB
Boone, L
DeAnda, F
Watson, C
Kenakin, T
[J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2003, 11 (18) : 4155 - 4155
[13] Recent progress in discovery of small-molecule CCR5 chemokine receptor ligands as HIV-1 inhibitors
Kazmierski, W
Bifulco, N
Yang, HB
Boone, L
DeAnda, F
Watson, C
Kenakin, T
[J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2003, 11 (13) : 2663 - 2676
[14] KAZMIERSKI W, 2006, 232 ACS NAT M SAN FR
[15] Small Molecule CCR5 and CXCR4-Based Viral Entry Inhibitors for Anti-HIV Therapy Currently in Development
Kazmierski, Wieslaw M.
Gudmundsson, Kristjan S.
Piscitelli, Stephen C.
[J]. ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 42, 2007, 42 : 301 - 320
[16] Kazmierski Wieslaw M., 2005, Current Medicinal Chemistry - Anti-Infective Agents, V4, P133, DOI 10.2174/1568012053506981
[17] Kazmierski Wieslaw M., 2002, Current Drug Targets - Infectious Disorders, V2, P265, DOI 10.2174/1568005023342489
[18] Peptide, peptidomimetic and small-molecule drug discovery targeting HIV-1 host-cell attachment and entry through gp120, gp41, CCR5 and CXCR4
Kazmierski, WM
Kenakin, TP
Gudmundsson, KS
[J]. CHEMICAL BIOLOGY & DRUG DESIGN, 2006, 67 (01) : 13 - 26
[19] KAZMIERSKI WM, 2004, Patent No. 2004054974
[20] Design, synthesis, and SAR of heterocycle-containing antagonists of the human CCR5 receptor for the treatment of HIV-1 infection
Kim, D
Wang, LP
Caldwell, CG
Chen, P
Finke, PE
Oates, B
MacCoss, M
Mills, SG
Malkowitz, L
Gould, SL
DeMartino, JA
Springer, MS
Hazuda, D
Miller, M
Kessler, J
Danzeisen, R
Carver, G
Carella, A
Holmes, K
Lineberger, J
Schleif, WA
Emini, EA
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (24) : 3103 - 3106

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