Potent tetracyclic guanine inhibitors of PDE1 and PDE5 cyclic guanosine monophosphate phosphodiesterases with oral antihypertensive activity

被引：71

作者：

Ahn, HS ^{[1
]}

Bercovici, A ^{[1
]}

Boykow, G ^{[1
]}

Bronnenkant, A ^{[1
]}

Chackalamannil, S ^{[1
]}

Chow, J ^{[1
]}

Cleven, R ^{[1
]}

Cook, J ^{[1
]}

Czarniecki, M ^{[1
]}

Domalski, C ^{[1
]}

Fawzi, A ^{[1
]}

Green, M ^{[1
]}

Gundes, A ^{[1
]}

Ho, G ^{[1
]}

Laudicina, M ^{[1
]}

Lindo, N ^{[1
]}

Ma, K ^{[1
]}

Manna, M ^{[1
]}

McKittrick, B ^{[1
]}

Mirzai, B ^{[1
]}

Nechuta, T ^{[1
]}

Neustadt, B ^{[1
]}

Puchalski, C ^{[1
]}

Pula, K ^{[1
]}

Silverman, L ^{[1
]}

Smith, E ^{[1
]}

Stamford, A ^{[1
]}

Tedesco, RP ^{[1
]}

Tsai, HG ^{[1
]}

Tulshian, D ^{[1
]}

Vaccaro, H ^{[1
]}

Watkins, RW ^{[1
]}

Weng, XY ^{[1
]}

Witkowski, JT ^{[1
]}

Xia, Y ^{[1
]}

Zhang, HT ^{[1
]}

机构：

[1] SCHERING PLOUGH CORP, RES INST, KENILWORTH, NJ 07033 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1997年 / 40卷 / 14期

关键词：

D O I：

10.1021/jm9608467

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Tetracyclic guanines have been shown to be potent and selective inhibitors of the cGMP-hydrolyzing enzymes PDE1 and PDE5. In general, these compounds are inactive or only weakly active as inhibitors of PDE3, which is a major isozyme involved in cAMP hydrolysis. Structure-activity relationships are developed at N-1, C-2, N-3, and N-5 on the core nucleus. Compound 31, with an IC50 of 70 pM, is the most potent inhibitor of PDE1, while 50, with an IC50 of 4 nM, is the most potent inhibitor of PDE5. Compounds 20, 22, 30, and 50 are potent dual inhibitors with IC50 values below 30 nM for both PDE1 and PDE5. Compounds 12, 20, and 28 reduced blood pressure by more than 45 mmHg when administered orally at 10 mg/kg to the spontaneously hypertensive rat (SHR).

引用

页码：2196 / 2210

页数：15

共 20 条

[1] AHN HS, 1989, BIOCHEM PHARMACOL, V38, P3331
[2] CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES - FUNCTIONAL IMPLICATIONS OF MULTIPLE ISOFORMS
BEAVO, JA
[J]. PHYSIOLOGICAL REVIEWS, 1995, 75 (04) : 725 - 748
[3] Inhibitors of types I and V phosphodiesterase: Elevation of cGMP as a therapeutic strategy
Czarniecki, M
Ahn, HS
Sybertz, EJ
[J]. ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 31, 1996, 31 : 61 - 70
[4] THE OXIDATION OF 6-ARYL-4(3H)-PTERIDINONES AND 7-ARYL-4(3H)-PTERIDINONES BY IMMOBILIZED ARTHROBACTER M-4 CELLS CONTAINING XANTHINE-OXIDASE
DEMEESTER, JWG
VANDERPLAS, HC
MIDDELHOVEN, WJ
[J]. JOURNAL OF HETEROCYCLIC CHEMISTRY, 1987, 24 (02) : 441 - 451
[5] PURINE STUDIES .23. CONFORMATIONAL ASPECTS OF N-(6-AMINO-2,4-DIOXO-1,2,3,4-TETRAHYDROPYRIMIDIN-5-YL)-FORMAMIDES AND RELATED N-BENZYL DERIVATIVES
FENN, MD
LISTER, JH
[J]. AUSTRALIAN JOURNAL OF CHEMISTRY, 1980, 33 (07) : 1611 - 1617
[6] HARRISON SA, 1986, MOL PHARMACOL, V29, P506
[7] MCMAHON EG, 1989, J PHARMACOL EXP THER, V251, P1000
[8] NEUSTADT B, 1995, Patent No. 5393755
[9] A CONVENIENT METHOD FOR OBTAINING TRANS-2-AMINOCYCLOHEXANOL AND TRANS-2-AMINOCYCLOPENTANOL IN ENANTIOMERICALLY PURE FORM
OVERMAN, LE
SUGAI, S
[J]. JOURNAL OF ORGANIC CHEMISTRY, 1985, 50 (21) : 4154 - 4155
[10] SAEKI T, 1995, J PHARMACOL EXP THER, V272, P825

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