Optimization of piperidyl-ureas as inhibitors of soluble epoxide hydrolase.
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.
Eldrup
Anne B
AB
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT 06877, United States. anne.eldrup@boehringer-ingelheim.com
Soleymanzadeh
Fariba
F
Farrow
Neil A
NA
Kukulka
Alison
A
De Lombaert
Stéphane
S
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry*; D051381:Rats; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics
D004791:Enzyme Inhibitors; D010880:Piperidines; C032727:piperidine; D014508:Urea; D004851:Epoxide Hydrolases