title: Development of a liver-targeted stearoyl-CoA desaturase (SCD) inhibitor (MK-8245) to establish a therapeutic window for the treatment of diabetes and dyslipidemia.
abstract: The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, Québec H9H 3L1, Canada. renataoballa@dhanni.com
authors.forename: Renata M
authors.initials: RM
authors.lastname: Oballa
authors.forename: Liette
authors.initials: L
authors.lastname: Belair
authors.forename: W Cameron
authors.initials: WC
authors.lastname: Black
authors.forename: Kelly
authors.initials: K
authors.lastname: Bleasby
authors.forename: Chi Chung
authors.initials: CC
authors.lastname: Chan
authors.forename: Carole
authors.initials: C
authors.lastname: Desroches
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Du
authors.forename: Robert
authors.initials: R
authors.lastname: Gordon
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Guay
authors.forename: Sebastien
authors.initials: S
authors.lastname: Guiral
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hafey
authors.forename: Emelie
authors.initials: E
authors.lastname: Hamelin
authors.forename: Zheng
authors.initials: Z
authors.lastname: Huang
authors.forename: Brian
authors.initials: B
authors.lastname: Kennedy
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lachance
authors.forename: France
authors.initials: F
authors.lastname: Landry
authors.forename: Chun Sing
authors.initials: CS
authors.lastname: Li
authors.forename: Joseph
authors.initials: J
authors.lastname: Mancini
authors.forename: Denis
authors.initials: D
authors.lastname: Normandin
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pocai
authors.forename: David A
authors.initials: DA
authors.lastname: Powell
authors.forename: Yeeman K
authors.initials: YK
authors.lastname: Ramtohul
authors.forename: Kathryn
authors.initials: K
authors.lastname: Skorey
authors.forename: Dan
authors.initials: D
authors.lastname: Sørensen
authors.forename: Wayne
authors.initials: W
authors.lastname: Sturkenboom
authors.forename: Angela
authors.initials: A
authors.lastname: Styhler
authors.forename: Deena M
authors.initials: DM
authors.lastname: Waddleton
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Simon
authors.initials: S
authors.lastname: Wong
authors.forename: Lijing
authors.initials: L
authors.lastname: Xu
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004058:Diffusion; D004285:Dogs; D005260:Female; D006243:Harderian Gland / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology*; D027381:Liver-Specific Organic Anion Transporter 1; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000378:metabolism; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013045:Species Specificity; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: C561635:(5-(3-(4-(2-bromo-5-fluorophenoxy)piperidin-1-yl)isoxazol-5-yl)-2H-tetrazol-2-yl)acetic acid; D000085:Acetates; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013777:Tetrazoles; D013230:Stearoyl-CoA Desaturase