Discovery of Novel and Potent Leukotriene B4 Receptor Antagonists. Part 1

被引：11

作者：

Goodnow, Robert A., Jr. ^{[1
]}

Hicks, Alexandra ^{[2
]}

Sidduri, Achyutharao ^{[1
]}

Kowalczyk, Agnieszka ^{[1
]}

Dominique, Romyr ^{[1
]}

Qiao, Qi ^{[1
]}

Lou, Jian Ping ^{[1
]}

Gillespie, Paul ^{[1
]}

Fotouhi, Nader ^{[1
]}

Tilley, Jefferson ^{[1
]}

Cohen, Noal ^{[1
]}

Choudhry, Satish ^{[3
]}

Cavallo, Gary

Tannu, Shahid A. ^{[2
]}

Ventre, Jessica D. ^{[2
]}

Lavelle, Danielle ^{[2
]}

Tare, Nadine S.

Oh, Hyesun ^{[4
]}

Lamb, Martin ^{[4
]}

Kurylko, Grazyna ^{[5
]}

Hamid, Rachid ^{[5
]}

Wright, Matthew B. ^{[5
]}

Pamidimukkala, Anjula ^{[4
]}

Egan, Thomas ^{[4
]}

Gubler, Ueli ^{[5
]}

Hoffman, Ann F. ^{[5
]}

Wei, Xin ^{[6
]}

Li, Ying L.

O'Neil, John ^{[7
]}

Marcano, Ruben ^{[7
]}

Pozzani, Karen ^{[7
]}

Molinaro, Tina ^{[7
]}

Santiago, Jennifer ^{[7
]}

Singer, Laura ^{[7
]}

Hargaden, Maureen ^{[7
]}

Moore, David

Catala, A. Robert ^{[4
]}

Chao, Lisa C. F. ^{[8
]}

Hermann, Gesine

Venkat, Radhika ^{[9
,10
]}

Mancebo, Helena ^{[10
]}

Renzetti, Louis M. ^{[2
]}

机构：

[1] Roche Res Ctr, Dept Disvcovery Chem, Nutley, NJ 07110 USA

[2] Roche Res Ctr, Dept RNA Therapeut, Nutley, NJ 07110 USA

[3] Roche Res Ctr, Dept Chem Synth, Nutley, NJ 07110 USA

[4] Roche Res Ctr, Dept Non Clin Safety, Nutley, NJ 07110 USA

[5] Roche Res Ctr, Dept Discovery Technol, Nutley, NJ 07110 USA

[6] Roche Res Ctr, Dept In Silico Sci, Nutley, NJ 07110 USA

[7] Roche Res Ctr, Dept Lab Anim Resources, Nutley, NJ 07110 USA

[8] Roche Res Ctr, PDR Lifecycle Management, Nutley, NJ 07110 USA

[9] ChemOvat Ltd, Horsham RH12 4QD, W Sussex, England

[10] Multispan Inc, Hayward, CA 94545 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 09期

关键词：

IN-VIVO; DESIGN; ASSAYS; DRUGS; CELLS; VITRO; BLT2;

D O I：

10.1021/jm1001919

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The inhibition of LTB4 binding to and activation of G-protein-coupled receptors BLT1 and BLT2 is the premise of a treatment for several inflammatory diseases. In a lead optimization effort starting with the leukotriene B-4 (LTB4) receptor antagonist (2), members of a series of 3,5-diarylphenyl ethers were found to be highly potent inhibitors of LTB4 binding to BLT1 and BLT2 receptors, with varying levels of selectivity depending on the substitution. In addition, compounds 33 and 38 from this series have good in vitro ADME properties, good oral bioavailability, and efficacy after oral delivery in guinea pig LTB4 and nonhuman primate allergen challenge models. Further profiling in a rat non-GLP toxicity experiment provided the rationale for differentiation and selection of one compound (33) for clinical development.

引用

页码：3502 / 3516

页数：15

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