期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 48, 期 10, 页码 3621-3629出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm0500929
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资金
- NHLBI NIH HHS [R01 HL059699, R01 HL59699-06A1] Funding Source: Medline
- NIDDK NIH HHS [P30 DK35747, P30 DK035747] Funding Source: Medline
- NIEHS NIH HHS [P01 ES11269, P30 ES05707, R37 ES002710, P42 ES004699, P01 ES011269, P30 ES005707, R37 ES02710, P42 ES-04699] Funding Source: Medline
Soluble epoxide hydrolase (sEH) plays an important role in the metabolism of endogenous chemical mediators involved in the regulation of blood pressure and inflammation. 1,3-Disubstituted ureas with a polar group located on the fifth atom from the carbonyl group of urea function are active inhibitors of sEH both in vitro and in vivo. However, their limited solubility in water and relatively high melting point lead to difficulties in formulating the compounds and poor in vivo efficacy. To improve these physical properties, the effect of structural modification of the urea pharmacophore on the inhibition potencies, water solubilities, octanol/water partition coefficients (log P), and melting points of a series of compounds was evaluated. For murine sEH, no loss of inhibition potency was observed when the urea pharmacophore was modified to an amide function, while for human sEH 2.5-fold decreased inhibition was obtained in the amide compounds. In addition, a NH group on the right side of carbonyl group of the amide pharmacophore substituted with an adamantyl group (such as compound 14) and a methylene carbon present between the adamantyl and amide groups were essential to produce potent inhibition of sEH. The resulting amide inhibitors have 10-30-fold better solubility and lower melting point than the corresponding urea compounds. These findings will facilitate synthesis of sEH inhibitors that are easier to formulate and more bioavailable.
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