Optimization of piperidyl-ureas as inhibitors of soluble epoxide hydrolase |
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Authors: | Anne B Eldrup Fariba Soleymanzadeh Neil A Farrow Alison Kukulka Stéphane De Lombaert |
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Institution: | Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT 06877, United States |
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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. |
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