Inhibitors of epoxide hydrolases for the treatment of...

Details Inhibitors of epoxide hydrolases for the treatment of... Inhibitors of epoxide hydrolases for the treatment of...

2002-12-23

2004-02-17

Reamer, James H (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C435S007920

Reexamination Certificate

active

06693130

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention generally relates to methods of treating hypertension using inhibitors of epoxide hydrolases. Preferred inhibitors include compounds, such as ureas, amides, and carbamates that can interact with the enzyme catalytic site and mimic transient intermediates. Other useful inhibitors include glycodiols and chalcone oxides which can interact with the enzyme as irreversible inhibitors.
2. Background of the Invention
Hypertension is the most common risk factor for cardiovascular disease, the leading cause of death in many developed countries. Essential hypertension, the most common form of hypertension, is usually defined as high blood pressure in which secondary causes such as renovascular disease, renal failure, pheochromocytoma, aldosteronism, or other causes are not present (for a discussion of the definition and etiology of essential hypertension see, Carretero and Oparil
Circulation
101:329-335 (2000) and Carretero, O. A. and S. Oparil.
Circulation
101:446-453 (2000)
A combination of genetic and environmental factors contribute to the development of hypertension and its successful treatment is limited by a relatively small number of therapeutic targets for blood pressure regulation. Renal cytochrome P450 (CYP) eicosanoids have potent effects on vascular tone and tubular ion and water transport and have been implicated in the control of blood pressure (Makita et al.
FASEB J
10:1456-146, (1996)). The major products of CYP-catalyzed arachidonic acid metabolism are regio- and stereoisomeric epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE produces potent vasoconstriction by inhibition of the opening of a large-conductance, calcium-activated potassium channel leading to arteriole vascular smooth muscle depolarization (Zou et al.
Am J. Physiol.
270:R228-237 (1996)). In contrast, the EETs have vasodilatory properties associated with an increased open-state probability of a calcium-activated potassium channel and hyperpolarization of the vascular smooth muscle and are recognized as putative endothelial derived hyperpolarizing factors (Campbell et al.
Cir. Res.
78:415-423 (1996)). Hydrolysis of the EETs to the corresponding dihydroxyeicosatrienoic acids (DHETs) is catalyzed largely by soluble epoxide hydrolase (sEH) (Zeldin et al.
J. Biol. Chem.
268:6402-64-07 (1993)).
Recent studies have indicated that renal CYP-mediated 20-HETE and EET formation are altered in genetic rat models of hypertension and that modulation of these enzyme activities is associated with corresponding changes in blood pressure (Omata et al.
Am J. Physiol
262:F8-16 (1992); Makita et al.
J Clin Invest
94:2414-2420 (1994); Kroetz et al.
Mol Pharmacol
52:362-372 (1997); Su, P. et al.,
Am J Physiol
275, R426-438 (1998)). Modulation of the CYP pathways of arachidonic acid metabolism as a means to regulate eicosanoid levels is limited by multiple isoforms contributing to a single reaction and the general lack of selectivity of most characterized inhibitors and inducers. Similarly, modulating EET levels by regulation of their hydrolysis to the less active diols has not been considered in light of concerns that EETs are involved in many physiological processes. (Campbell,
Trends Pharmacol Sci
21:125-7 (2000)).
SUMMARY OF THE INVENTION
The present invention provides method s of treating hypertension by administering to a patient a therapeutically effective amount of an inhibitor of epoxide hydrolase. A preferred class of compounds for practice in accordance with the invention has the structure shown by Formula 1.
wherein Z is oxygen or sulfur, W is carbon phosphorous or sulfur, X and Y is each independently nitrogen, oxygen, or sulfur, and X can further be carbon, at least one of R
1
-R
4
is hydrogen, R
2
is hydrogen when X is nitrogen but is not present when X is sulfur or oxygen, R
4
is hydrogen when Y is nitrogen but is not present when Y is sulfur or oxygen, R
1
and R
3
are each independently a substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl, acyl, or heterocyclic.
Preferred compound of the invention have an IC
50
(inhibition potency or, by definition, the concentration of inhibitor which reduces enzyme activity by 50%) of less than about 500 &mgr;M. Exemplary compounds of the invention are listed in Table 1. Table shows inhibition of recombinant mouse sEH (MsEH) and Human sEH (HsEH). The enzyme concentrations were 0.13 and 0.26 micromolar respectively
TABLE 1
Inhibition of MsEH (0.13 &mgr;M) and HsEH (0.26 &mgr;M)
Mouse sEH
Human sEH
Structure inhibitors
nb
IC
50
(&mgr;M)*
IC
50
(&mgr;M)*
72
0.11 ± 0.01
0.48 ± 0.01

248
0.33 ± 0.05
2.9 ± 0.6

42
0.06 ± 0.01
0.13 ± 0.01

224
0.99 ± 0.02
0.32 ± 0.08

225
0.84 ± 0.10
1.05 ± 0.03

276
1.1 ± 0.1
0.34 ± 0.02

277
0.12 ± 0.01
0.22 ± 0.02

460
0.10 ± 0.02
0.18 ± 0.01

110
0.21 ± 0.01
0.35 ± 0.01

259
0.45 ± 0.09
0.10 ± 0.02

260
0.06 ± 0.01
0.10 ± 0.01

261
0.08 ± 0.01
0.12 ± 0.01

262
0.05 ± 0.01
0.10 ± 0.02

263
3.0 ± 0.3
0.33 ± 0.06

255
0.48 ± 0.07
2.88 ± 0.04

514
0.27 ± 0.01

515
0.19 ± 0.05

187
0.05 ± 0.01
0.42 ± 0.03

374
0.25 ± 0.01
2.03 ± 0.07

381
0.06 ± 0.01
0.68 ± 0.03

0.25 ± 0.02
0.47 ± 0.01

189
0.80 ± 0.03
1.0 ± 0.2

375
0.18 ± 0.01
0.11 ± 0.01

157
0.85 ± 0.01
1.43 ± 0.03

143
1.0 ± 0.1
0.57 ± 0.01

178
0.31 ± 0.01
0.25 ± 0.01

380
0.73 ± 0.03
0.68 ± 0.03

125
0.09 ± 0.01
0.72 ± 0.02

183
1.06 ± 0.07
5.9 ± 0.3

175
0.24 ± 0.01

181
0.52 ± 0.02
1.71 ± 0.23

168
0.06 ± 0.01
0.12 ± 0.01

151
2.29 ± 0.03
0.58 ± 0.01

170
0.12 ± 0.01
0.18 ± 0.01

429
0.38 ± 0.04
1.7 ± 0.4

153
0.06 ± 0.01
0.10 ± 0.01

148
0.21 ± 0.01
0.61 ± 0.02

172
0.12 ± 0.01
0.30 ± 0.01

556
0.20 ± 0.02
0.74 ± 0.07

478
0.05 ± 0.01
0.26 ± 0.02

562
0.5 ± 0.1
15 ± 3 

531
0.14 ± 0.02
0.64 ± 0.03

504
0.8 ± 0.1
23 ± 4 

479
0.60 ± 0.06
5.0 ± 0.1

103
0.12 ± 0.01
2.2 ± 0.1

347
0.07 ± 0.01
3.10 ± 0.07

124
0.05 ± 0.01
0.14 ± 0.01

509
0.06 ± 0.01
0.92 ± 0.08

286
0.11 ± 0.03
0.07 ± 0.02

344
0.05 ± 0.01
2.50 ± 0.08

508
0.05 ± 0.01
0.10 ± 0.01

473
0.05 ± 0.01
0.10 ± 0.01

297
0.05 ± 0.01
0.10 ± 0.01

425
0.05 ± 0.01
0.10 ± 0.01

354
0.05 ± 0.01
0.10 ± 0.01

477
0.11 ± 0.01
0.24 ± 0.01

23
0.10 ± 0.01
1.69 ± 0.05

0.09 ± 0.01
0.16 ± 0.01

538
0.05 ± 0.01
0.10 ± 0.01

551
0.05 ± 0.01
0.10 ± 0.01

57
0.06 ± 0.01
0.16 ± 0.01

360
0.05 ± 0.01
0.10 ± 0.01

359
0.05 ± 0.01
0.10 ± 0.01

461
0.42 ± 0.01
0.55 ± 0.02

533
0.05 ± 0.1
0.10 ± 0.01

463
0.90 ± 0.07
8.3 ± 0.4

377
0.7 ± 0.1
17.8 ± 0.7 

428
0.05 ± 0.1
0.10 ± 0.01

22
0.05 ± 0.1
0.10 ± 0.01

58
0.05 ± 0.01
0.09 ± 0.01

119
0.05 ± 0.01
0.10 ± 0.01

543
0.05 ± 0.01
0.10 ± 0.01

192
0.05 ± 0.01
0.10 ± 0.01

427
0.05 ± 0.01
0.10 ± 0.01

358
0.05 ± 0.01
0.18 ± 0.04

21
0.76 ± 0.02
1.39 ± 0.02

435
0.05 ± 0.01
0.18 ± 0.01

270
0.05 ± 0.01
1.9 ± 0.1

544
0.05 ± 0.01
0.10 ± 0.01

545
0.05 ± 0.01
3.7 ± 0.3

437
0.05 &plusm

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