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Bioorg Med Chem Lett. 2010 Jan 15;20(2):571-5. doi: 10.1016/j.bmcl.2009.11.091. Epub 2009 Nov 22.

Optimization of piperidyl-ureas as inhibitors of soluble epoxide hydrolase.

Author information

1
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT 06877, United States. anne.eldrup@boehringer-ingelheim.com

Abstract

Inhibition of sEH is hypothesized to lead to an increase in epoxyeicosatrienoic acids resulting in the potentiation of their anti-inflammatory and vasodilatory effects. In an effort to explore sEH inhibition as an avenue for the development of vasodilatory and cardio- or renal-protective agents, a lead identified through high-throughput screening was optimized, guided by the determination of a solid state co-structure with sEH. Replacement of potential toxicophores was followed by optimization of cell-based potency and ADME properties to provide a new class of functionally potent sEH inhibitors with attractive in vitro metabolic profiles and high and sustained plasma exposures after oral administration in the rat.

PMID:
19969453
DOI:
10.1016/j.bmcl.2009.11.091
[Indexed for MEDLINE]

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