Substituted 4-(2,2-diphenylethyl)pyridine-N-oxides as phosphodiesterase-4 inhibitors:: SAR study directed toward the improvement of pharmacokinetic parameters

被引：21

作者：

Frenette, R ^{[1
]}

Blouin, M ^{[1
]}

Brideau, C ^{[1
]}

Chauret, N ^{[1
]}

Ducharme, Y ^{[1
]}

Friesen, RW ^{[1
]}

Hamel, P ^{[1
]}

Jones, TR ^{[1
]}

Laliberté, F ^{[1
]}

Li, C ^{[1
]}

Masson, P ^{[1
]}

McAuliffe, M ^{[1
]}

Girard, Y ^{[1
]}

机构：

[1] Merck Frosst Ctr Therapeut Res, Pointe Claire, PQ H9R 4P8, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2002年 / 12卷 / 20期

关键词：

D O I：

10.1016/S0960-894X(02)00615-7

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A detailed SAR study directed toward the optimization of pharmacokinetic parameters for analogues of L-791,943 is reported. The introduction of a soft metabolic site on this structure permitted the identification of L-826,141 as a potent phosphodiesterase type 4 (PDE4) inhibitor that is well absorbed and that presents a shorter half-life than L-791,943 in a variety of animal species. The efficacy of L-826,141 is also demonstrated in different in vivo models. (C) 2002 Elsevier Science Ltd. All rights reserved.

引用

页码：3009 / 3013

页数：5

共 26 条

[1] THE 5-LIPOXYGENASE INHIBITOR ZILEUTON BLOCKS ANTIGEN-INDUCED LATE AIRWAY RESPONSES, INFLAMMATION AND AIRWAY HYPERRESPONSIVENESS IN ALLERGIC SHEEP [J].

ABRAHAM, WM ;

AHMED, A ;

CORTES, A ;

SIELCZAK, MW ;

HINZ, W ;

BOUSKA, J ;

LANNI, C ;

BELL, RL .

EUROPEAN JOURNAL OF PHARMACOLOGY, 1992, 217 (2-3) :119-126

[2]

Barnard A, 2000, J ROY ANTHROPOL INST, V6, P164

[3]

Barnette MS, 1998, J PHARMACOL EXP THER, V284, P420

[4] The effects of phosphodiesterase type 4 inhibitors on tumour necrosis factor-α and leukotriene B4 in a novel human whole blood assay [J].

Brideau, C ;

Van Staden, C ;

Styhler, A ;

Rodger, IW ;

Chan, CC .

BRITISH JOURNAL OF PHARMACOLOGY, 1999, 126 (04) :979-988

[5] Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study [J].

Compton, CH ;

Gubb, J ;

Nieman, R ;

Edelson, J ;

Amit, O ;

Bakst, A ;

Ayres, JG ;

Creemers, JPHM ;

Schultze-Werninghaus, G ;

Brambilla, C ;

Barnes, NC .

LANCET, 2001, 358 (9278) :265-270

[6]

Conti M, 2000, PROG NUCLEIC ACID RE, V63, P1

[7] INHIBITION OF EOSINOPHIL CYCLIC-NUCLEOTIDE PDE ACTIVITY AND OPSONISED ZYMOSAN-STIMULATED RESPIRATORY BURST BY TYPE-IV-SELECTIVE PDE INHIBITORS [J].

DENT, G ;

GIEMBYCZ, MA ;

RABE, KF ;

BARNES, PJ .

BRITISH JOURNAL OF PHARMACOLOGY, 1991, 103 (02) :1339-1346

[8] Discovery of L-791,943:: A potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor [J].

Guay, D ;

Hamel, P ;

Blouin, M ;

Brideau, C ;

Chan, CC ;

Chauret, N ;

Ducharme, Y ;

Huang, Z ;

Girard, M ;

Jones, TR ;

Laliberté, F ;

Masson, P ;

McAuliffe, M ;

Piechuta, H ;

Silva, J ;

Young, RN ;

Girard, Y .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (11) :1457-1461

[9] Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis [J].

Hanifin, JM ;

Chan, SC ;

Cheng, JB ;

Tofte, SJ ;

Henderson, WR ;

Kirby, DS ;

Weiner, ES .

JOURNAL OF INVESTIGATIVE DERMATOLOGY, 1996, 107 (01) :51-56

[10] The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects [J].

Harbinson, PL ;

MacLeod, D ;

Hawksworth, R ;

OToole, S ;

Sullivan, PJ ;

Heath, P ;

Kilfeather, S ;

Page, CP ;

Costello, J ;

Holgate, ST ;

Lee, TH .

EUROPEAN RESPIRATORY JOURNAL, 1997, 10 (05) :1008-1014

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