Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors

被引：121

作者：

Holladay, MW ^{[1
]}

Wasicak, JT ^{[1
]}

Lin, NH ^{[1
]}

He, Y ^{[1
]}

Ryther, KB ^{[1
]}

Bannon, AW ^{[1
]}

Buckley, MJ ^{[1
]}

Kim, DJB ^{[1
]}

Decker, MW ^{[1
]}

Anderson, DJ ^{[1
]}

Campbell, JE ^{[1
]}

Kuntzweiler, TA ^{[1
]}

Donnelly-Roberts, DL ^{[1
]}

Piattoni-Kaplan, M ^{[1
]}

Briggs, CA ^{[1
]}

Williams, M ^{[1
]}

Arneric, SP ^{[1
]}

机构：

[1] Abbott Labs, Neurol & Urol Dis Res D47W, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 04期

关键词：

D O I：

10.1021/jm9706224

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

New members of a previously reported series of 3-pyridyl ether compounds are disclosed as novel, potent analgesic agents acting through neuronal nicotinic acetylcholine receptors. Both (R)-2-chloro-5-(2-azetidinylmethoxy)pyridine (ABT-594, 5) and its S-enantiomer (4) show potent analgesic activity in the mouse hot-plate assay following either intraperitoneal (ip) or oral (po) administration, as well as activity in the mouse abdominal constriction (writhing) assay, a model of persistent pain. Compared to the S-enantiomer and to the prototypical potent nicotinic analgesic agent (+/-)-epibatidine, 5 shows diminished activity in models of peripheral side effects. Structure-activity studies of analogues related to 4 and 5 suggest that the N-unsubstituted azetidine moiety and the 2-chloro substituent on the pyridine ring are important contributors to potent analgesic activity.

引用

页码：407 / 412

页数：6

共 4 条

[1] ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]:: A novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors:: I.: In vitro characterization
Donnelly-Roberts, DL
Puttfarcken, PS
Kuntzweiler, TA
Briggs, CA
Anderson, DJ
Campbell, JE
Piattoni-Kaplan, M
McKenna, DG
Wasicak, JT
Holladay, MW
Williams, M
Arneric, SP
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 1998, 285 (02): : 777 - 786
[2] ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]:: A novel, orally effective antinociceptive agent acting via neuronal nicotinic acetylcholine receptors:: II.: In vivo characterization
Bannon, AW
Decker, MW
Curzon, P
Buckley, MJ
Kim, DJB
Radek, RJ
Lynch, JK
Wasicak, JT
Lin, NH
Arnold, WH
Holladay, MW
Williams, M
Arneric, SP
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 1998, 285 (02): : 787 - 794
[3] Anti-inflammatory activity of ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: A novel, non-opioid nicotinic acetylcholine receptor agonist.
Jacobson, PB
Komater, V
Wilcox, DM
Namovic, MT
Harris, RR
Decker, MW
Holladay, MW
Arueric, SP
FASEB JOURNAL, 1998, 12 (05): : A761 - A761
[4] SYNTHESIS, STRUCTURE-ACTIVITY-RELATIONSHIPS, AND PHARMACOLOGICAL EVALUATION OF A SERIES OF FLUORINATED 3-BENZYL-5-INDOLECARBOXAMIDES - IDENTIFICATION OF 4-[[5-[((2R)-2-METHYL-4,4,4-TRIFLUOROBUTYL)CARBAMOYL]-1-METHYLINDOL-3-YL]METHYL]-3-METHOXY-N-[(2-METHYLPHENYL)SULFONYL]BENZAMIDE, A POTENT, ORALLY-ACTIVE ANTAGONIST OF LEUKOTRIENES D(4) AND E(4)
JACOBS, RT
BERNSTEIN, PR
CRONK, LA
VACEK, EP
NEWCOMB, LF
AHARONY, D
BUCKNER, CK
KUSNER, EJ
JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (09) : 1282 - 1297

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