title: Design and synthesis of substituted nicotinamides as inhibitors of soluble epoxide hydrolase.
abstract: A series of potent nicotinamide inhibitors of soluble epoxides hydrolase (sEH) is disclosed. This series was designed using structure-based deconstruction and a combination of two HTS hit series, resulting in hybrid analogs that retained the optimal potency from one series, and acceptable in vitro metabolic stability from the other. Structure-guided optimization of these analogs gave rise to nanomolar inhibitors of human sEH that had acceptable plasma exposure to qualify them as probes to determine the in vivo phenotypic consequences of sEH inhibition.
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd. PO Box 368, Ridgefield, CT 06877-036, USA. steven.taylor@boehringer-ingelheim.com
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Taylor
authors.forename: Fariba
authors.initials: F
authors.lastname: Soleymanzadeh
authors.forename: Anne B
authors.initials: AB
authors.lastname: Eldrup
authors.forename: Neil A
authors.initials: NA
authors.lastname: Farrow
authors.forename: Ingo
authors.initials: I
authors.lastname: Muegge
authors.forename: Alison
authors.initials: A
authors.lastname: Kukulka
authors.forename: Alisa K
authors.initials: AK
authors.lastname: Kabcenell
authors.forename: Stephane
authors.initials: S
authors.lastname: De Lombaert
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D009536:Niacinamide / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D009536:Niacinamide; D004851:Epoxide Hydrolases