title: Nicotinic acids: liver-targeted SCD inhibitors with preclinical anti-diabetic efficacy.
abstract: An in vitro screening protocol was used to transform a systemically-distributed SCD inhibitor into a liver-targeted compound. Incorporation of a key nicotinic acid moiety enables molecular recognition by OATP transporters, as demonstrated by uptake studies in transfected cell lines, and likely serves as a critical component of the observed liver-targeted tissue distribution profile. Preclinical anti-diabetic oGTT efficacy is demonstrated with nicotinic acid-based, liver-targeting SCD inhibitor 10, and studies with a close-structural analog devoid of SCD1 activity, suggest this efficacy is a result of on-target activity.
authors: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Québec, Canada H9H 3L1. david_powell2@merck.com
authors: David A
authors: DA
authors: Powell
authors: W Cameron
authors: WC
authors: Black
authors: Kelly
authors: K
authors: Bleasby
authors: Chi-Chung
authors: CC
authors: Chan
authors: Denis
authors: D
authors: Deschenes
authors: Marc
authors: M
authors: Gagnon
authors: Rob
authors: R
authors: Gordon
authors: Jocelyne
authors: J
authors: Guay
authors: Sebastien
authors: S
authors: Guiral
authors: Michael J
authors: MJ
authors: Hafey
authors: Zheng
authors: Z
authors: Huang
authors: Elise
authors: E
authors: Isabel
authors: Yves
authors: Y
authors: Leblanc
authors: Angela
authors: A
authors: Styhler
authors: Li-Jing
authors: LJ
authors: Xu
authors: Lei
authors: L
authors: Zhang
authors: Renata M
authors: RM
authors: Oballa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D009539:Nicotinic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D009539:Nicotinic Acids; D013230:Stearoyl-CoA Desaturase