title: Discovery and pharmacological characterization of SAR707 as novel and selective small molecule inhibitor of stearoyl-CoA desaturase (SCD1).
abstract: Stearoyl-CoA desaturase (SCD1) is linked to the pathogenesis of obesity, dyslipidemia and type 2 diabetes. It is the rate-limiting enzyme in the synthesis of monounsaturated 16:1 n-7 and 18:1 n-9 fatty acyl-CoAs and catalyzes an essential part of lipogenesis. Here, we describe the identification, in vitro properties and in vivo efficacy of a novel class of heterocyclic small molecule hexahydro-pyrrolopyrrole SCD1 inhibitors. SAR707, a compound representative for the series, was optimized to high in vitro potency, selectivity and favorable overall properties in enzymatic and cellular assays. In vivo, this compound reduced serum desaturation index, decreased body weight gain and improved lipid parameters and blood glucose levels of obese Zucker diabetic fatty rats treated for 4 weeks in a chronic study. In parallel, fissures of the eye lid, alopecia and inflammation of the skin were observed from day 11 on in all animals treated with the same metabolically active dose. In summary, we described in vitro and in vivo properties of a novel, potent and selective SCD1 inhibitor that improved body weight, blood glucose and triglycerides in an animal model of obesity, type 2 diabetes and dyslipidemia. However, the favorable in vivo properties of systemic SCD1 inhibition shown in our study were accompanied by dose-dependently occurring adverse target-related effects observed in skin. Thus, systemic SCD1 inhibition by small molecules might therefore not represent a feasible approach for the treatment of chronic metabolic diseases.
authors.affiliation: Sanofi-Aventis, Research and Development, Frankfurt am Main, Germany. marcdietrich.voss@sanofi.com
authors.forename: Marc D
authors.initials: MD
authors.lastname: Voss
authors.forename: Gerhard
authors.initials: G
authors.lastname: Zoller
authors.forename: Hans
authors.initials: H
authors.lastname: Matter
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Herling
authors.forename: Gabriele
authors.initials: G
authors.lastname: Biemer-Daub
authors.forename: Anja
authors.initials: A
authors.lastname: Pfenninger
authors.forename: Silke
authors.initials: S
authors.lastname: Haag-Diergarten
authors.forename: Stefanie
authors.initials: S
authors.lastname: Keil
authors.forename: Markus
authors.initials: M
authors.lastname: Kohlmann
authors.forename: Hans-Ludwig
authors.initials: HL
authors.lastname: Schmidts
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D009765:Obesity / Q000188:drug therapy; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors*; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D011724:Pyridazines; C584534:SAR707; D014280:Triglycerides; D013230:Stearoyl-CoA Desaturase