Stearoyl-CoA desaturase (SCD) is a key lipogenic enzyme involved in the biosynthesis of mono-unsaturated fatty acids. Its preferred substrates are long-chain acyl-CoAs, such as palmitoyl (16:0)-CoA and stearoyl (18:0)-CoA, which are de-saturated to give palmitoleoyl (16:1)-CoA and oleoyl (18:1)-CoA, respectively . These products, in turn, are the predominant mono-unsaturated fatty acid components of triglycerides, phospholipids, and cholesteryl- and wax-esters . Mono-unsaturated fatty acids also serve as components of signal transduction through effects on protein kinases and transcription factor activation. Therefore, changes in the activity or levels of SCD would be expected to alter lipoprotein metabolism, adiposity, membrane fluidity, and signal transduction.
To date, four murine isoforms of SCD (SCD1-4) have been identified [72-75]. Although the four isoforms share considerable sequence homology (>80% amino acid sequence identity) and catalyze the same biochemical transform, their tissue distribution varies. For example, SCD1 is expressed in lipogenic tissues, such as liver, adipose, and sebaceous glands . SCD2 is ubiquitously expressed in most tissues, with the exception of liver , while SCD3 is found in the Harderian gland  and SCD4 primarily in the heart . Additionally, two human SCD genes with > 85% homology to murine SCD1 have been identified [77,78].
SCDl-deficient asebia mice bred onto a leptin-deficient (ob/ob) background show reduced adiposity despite higher food intake and have a corrected hypo-metabolic phenotype, suggesting that down-regulation of SCD1 is an important component of leptin's metabolic actions . SCD1 knockout mice are viable and are resistant to diet-induced obesity, have lowered plasma VLDL and TG levels, and show increased energy expenditure and insulin sensitivity [80-82]. However, in addition to these favorable phenotypic components, SCDl-deficient mice develop cutaneous abnormalities including alopecia and narrow eye fissure . More recently, pharmacological inhibition of SCD1 in mice with SCD1 antisense oligonucleotides has recapitulated characteristics of the KO animal, such as the improved insulin sensitivity and resistance to diet-induced obesity, in the absence of alopecia .
A number of patent applications that describe small molecule inhibitors of SCD-1 have recently published. For example, a series of patent applications describe related piperazine-based inhibitors of SCD-1 (exemplified by 19) . Piperazine replacements, such as piperidine, 4-aminopiperidine, and 3-amino-azetidine are tolerated, as are thiadiazole and pyridine surrogates of the 1,2-diazine [86-90].
Constrained variants, such as 20 and 21 have also been reported [91,92]. Interestingly, the diazine-amide portion of 19 can be mimicked by the imidazo[1,2-b]pyridazine in 22 . Presently, work in this field remains at a pre-clinical stage.
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