Design and synthesis of substituted nicotinamides as inhibitors of soluble epoxide hydrolase.
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.
Taylor
Steven J
SJ
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd. PO Box 368, Ridgefield, CT 06877-036, USA. steven.taylor@boehringer-ingelheim.com
Soleymanzadeh
Fariba
F
Eldrup
Anne B
AB
Farrow
Neil A
NA
Muegge
Ingo
I
Kukulka
Alison
A
Kabcenell
Alisa K
AK
De Lombaert
Stephane
S
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
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D009536:Niacinamide; D004851:Epoxide Hydrolases