Synthesis and structure-activity relationships of a novel series of 2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide KATP channel openers:: Discovery of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), a potent KATP opener that selectively inhibits spontaneous bladder contractions

被引：44

作者：

Carroll, WA ^{[1
]}

Altenbach, RJ ^{[1
]}

Bai, H ^{[1
]}

Brioni, JD ^{[1
]}

Brune, ME ^{[1
]}

Buckner, SA ^{[1
]}

Cassidy, C ^{[1
]}

Chen, YY ^{[1
]}

Coghlan, MJ ^{[1
]}

Daza, AV ^{[1
]}

Drizin, I ^{[1
]}

Fey, TA ^{[1
]}

Fitzgerald, M ^{[1
]}

Gopalakrishnan, M ^{[1
]}

Gregg, RJ ^{[1
]}

Henry, RF ^{[1
]}

Holladay, MW ^{[1
]}

King, LL ^{[1
]}

Kort, ME ^{[1
]}

Kym, PR ^{[1
]}

Milicic, I ^{[1
]}

Tang, R ^{[1
]}

Turner, SC ^{[1
]}

Whiteaker, KL ^{[1
]}

Yi, L ^{[1
]}

Zhang, H ^{[1
]}

Sullivan, JP ^{[1
]}

机构：

[1] Abbott Labs, Neurosci Res, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 12期

关键词：

D O I：

10.1021/jm030356w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structure-activity relationships were investigated on a novel series of sulfonyldihydropyridine-containing K-ATP openers. Ring sizes, absolute stereochemistry, and aromatic substitution were evaluated for K-ATP activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a select group of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation. In an anesthetized pig model of myogenic bladder overactivity, compound 14 and (-)-cromakalim 1 were found to inhibit spontaneous bladder contractions in vivo at plasma concentrations lower than those that affected hemodynamic parameters. Compound 14 showed approximately 5-fold greater selectivity than I in vivo and supports the concept that bladder-selective K-ATP channel openers may have utility in the treatment of overactive bladder.

引用

页码：3163 / 3179

页数：17

共 35 条

[1]

ALDRED R, 1994, J CHEM SOC P1, V13, P1823

[2] The overactive bladder: Pharmacologic basis of drug treatment [J].

Andersson, KE .

UROLOGY, 1997, 50 (6A) :74-84

[3]

ASHIMORI A, 1990, CHEM PHARM BULL, V38, P2446

[4] The overactive bladder: current aetiological concepts [J].

Bosch, JLHR .

BJU INTERNATIONAL, 1999, 83 :7-9

[5] A myogenic basis for the overactive bladder [J].

Brading, AF .

UROLOGY, 1997, 50 (6A) :57-67

[6] Spontaneous phasic activity of the pig urinary bladder smooth muscle: characteristics and sensitivity to potassium channel modulators [J].

Buckner, SA ;

Milicic, I ;

Daza, AV ;

Coghlan, MJ ;

Gopalakrishnan, M .

BRITISH JOURNAL OF PHARMACOLOGY, 2002, 135 (03) :639-648

[7] Pharmacological and molecular analysis of ATP-sensitive K+ channels in the pig and human detrusor [J].

Buckner, SA ;

Milicic, I ;

Daza, A ;

Davis-Taber, R ;

Scott, VES ;

Sullivan, JP ;

Brioni, JD .

EUROPEAN JOURNAL OF PHARMACOLOGY, 2000, 400 (2-3) :287-295

[8] Design and SAR of novel potassium channel openers targeted for urge urinary incontinence.: 1.: N-cyanoguanidine bioisosteres possessing in vivo bladder selectivity [J].

Butera, JA ;

Antane, MM ;

Antane, SA ;

Argentieri, TM ;

Freeden, C ;

Graceffa, RF ;

Hirth, BH ;

Jenkins, D ;

Lennox, JR ;

Matelan, E ;

Norton, NW ;

Quagliato, D ;

Sheldon, JH ;

Spinelli, W ;

Warga, D ;

Wojdan, A ;

Woods, M .

JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (06) :1187-1202

[9] Recent developments in the biology and medicinal chemistry of potassium channel modulators: Update from a decade of progress [J].

Coghlan, MJ ;

Carroll, WA ;

Gopalakrishnan, M .

JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (11) :1627-1653

[10] SYNTHESIS OF NOVEL CYCLIC SULFONE DIHYDROPYRIDINES FACILITATED BY A SELECTIVE ETHYL DIAZOACETATE RING EXPANSION [J].

DODD, JH ;

SCHWENDER, CF ;

GRAYNUNEZ, Y .

JOURNAL OF HETEROCYCLIC CHEMISTRY, 1990, 27 (05) :1453-1456

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