SCDs are a family of microsomal Fe-based metalloenzymes. They act on long-chain saturated acyl CoAs and introduce a cis-double bond at the C-9 or C-10 position. For example, SCDs convert stearic acid into oleic acid, and palmitic acid into palmitoleic acid. Monounsaturated FAs constitute a major component of TGs, cholesteryl esters, and phospholipids. The reaction requires molecular O2 and NADH and generates H2O in the process [3,4].
Two isoforms (SCD1 and SCD5, also known as SCD2 in rodents) have been identified in humans. SCD1 is most highly expressed in liver, adipose tissue, and skeletal muscle  while SCD2 is found primarily in the brain . For this reason, in papers that utilize liver microsomes or cells as sources of SCD for assays, the terms SCD1 and SCD are often used interchangeably.
Deletion, mutation, or inhibition of SCD1 in mice and rats results in decreased hepatic TGs [7-11], resistance to weight gain, and improvements in insulin sensitivity and glucose uptake. In one study, naturally occurring lean, hypermetabolic SCD-deficient asebia mice were crossed with obese leptin-deficient ob/ob mice and the resulting offspring were lean, hyperme-tabolic and had normal liver histology . Thus, SCD inhibition may offer a novel approach to treating obesity, insulin resistance, and diabetes, as well as fatty liver diseases, such as steatosis and nonalcoholic steato-hepatatis (NASH) [12-16]. However, mechanism-based side effects have been reported and appear to be due to a deficit of unsaturated FAs in peripheral tissues like skin and pancreas [9,17]. Reported skin side effects included loss of hair (alopecia) and eye fissure . Additionally, using antisense oligonucleotides to inhibit SCD in a mouse model of hyperlipi-demia and atherosclerosis (LDLr-/- Apob100/100), it has been demonstrated that SCD inhibition increased atherosclerosis independently of improvements in obesity and insulin resistance and argued against SCD1 inhibition as a safe therapeutic approach for treatment of the metabolic syndrome . The development of atherosclerosis could not be prevented with dietary oleic acid. However, in a follow-up study, fish oils were able to fully prevent the development of atherosclerosis following SCD inhibition. It is proposed that fish oils antagonize the inflammatory effects of saturated FAs on the Toll4 receptor system .
The pursuit of SCD as a "druggable" target began in the early 2000s. In 2005, a series of patent applications emerged that are exemplified by compound 1. The common motif in the generic structures of these patent applications is a pair of linked nitrogen heterocycles, one aromatic and one saturated, for example, pyridazine and piperazine, flanked by amide-linked hydrophobic groups . This family of patents inspired a number of second-generation designs, such as A-939572 (2), featuring a bioisos-teric replacement of acylpiperazine with hydroxypiperidine. Compound 2 was found to be a potent SCD inhibitor (IC50 37 and <4 nM in human and mouse liver microsomal assays, respectively). Compound 2 also possessed very good mouse pharmacokinetic (PK) properties (F = 92%, Clp = 0.4 L/h/kg) and demonstrated efficacy in lowering the ratio of unsaturated to saturated FAs (desaturation index) in liver and plasma when administered to ob/ob mice . Unfortunately, in the same study, side effects consistent with asebia and the SCD knock-out mouse pheno-type were observed that included alopecia and eye fissure .
Other designs structurally related to those reported in the 2005 series of patent applications included thiazole derivative 3 and MF-438 (4). In the case of 3, the six-membered heteroaromatic ring in 1 was contracted to a five-membered ring, and the adjacent amide was replaced by a 1,2,4-oxadiazole bioisostere . In 4, a 1,3,4-thiadiazole was utilized . Compound 3 showed an SCD IC50 of 1 nM in both rat microsomal and human HEPG2 cell-based assays. The compound preferentially distributed into liver and adipose tissues compared to skin (3.7- and 4.9-fold respectively at 6 h postdose) and displayed efficacy for SCD inhibition in vivo. C57BL6 mice fed a high-fat diet that were dosed with 3 (0.2 mg/kg, qd, 28 days) displayed significantly reduced body weight gain compared to a high-fat-fed control group and had body weight gain similar to that of regular chow-fed mice. However, despite apparent tissue selectivity, skin and eye side effects consistent with the SCD knock-out phenotype were also observed beginning at approximately day 7 of the study.
Another group of researchers built on SAR from previously reported compounds including 1-4 and generated a lead compound, pyridazine 5. Similarly to 2, the piperazine ring of 1 was transformed into piperidine and the keto moiety was retained. The amide moiety in the left-hand portion of the molecule was retained, but similar to 3 addition of a hydroxy group was found to be beneficial. Introduction of a 3-pyridyl group contributed to potency (SCD IC50 = 37 nM, mouse microsomal assay), oral bioavailability (F = 68%, mouse), solubility (>100 jmM, pH 1.2), and oral efficacy of 5 for lowering the desaturase activity (ID50 = 3 mg/kg) . The same group reported a second-generation design (6), featuring a spirocyclic ring system that retained an ortho-CF3 substituent common to many SCD inhibitors. Compound 6 possessed superior potency for SCD inhibition in vitro (IC50 = 60 pM, mouse microsomal assay) and in vivo (ID50 0.5 and 0.8 mg/kg, 2-3 and 6-7 h after administration respectively) .
Additional leads were identified by independent screening efforts. The quinoxalinone CVT-13036 (7) had an SCD IC50 of 50 pM in a human HEPG2 assay, but lacked oral bioavailability . On the other hand, the quinazolinone CVT-11,563 (8) had excellent bioavailability (F = 90%, rat) but only a modest potency for SCD inhibition (IC50 = 268 nM, rat microsomal assay; IC50 = 68 nM, human HEPG2 cells) . CVT-12,012 (9) is an analog of 7 that incorporates the hydroxyacetyl group of 8. It had good potency for SCD inhibition and good oral bioavailability (IC50 = 119 nM, human HEPG2 cells, F = 78%). Compound 9 also showed good in vivo efficacy for reduction of the desaturation index and hepatic TGs in high-carbohydrate-fed rats (~50% reduction, 20 mg/kg, po bid, 5 d) . A pyrrolotriazinone analog of 8, CVT-12,805 (10), showed improved potency (SCD IC50 = 10 nM, rat microsomal assay) and good efficacy for the reduction in desaturation index when dosed orally to high-sucrose-fed mice .
Another independent high-throughput screening (HTS) and hit optimization effort resulted in the potent (SCD IC50 2 and 3 nM; mouse and human microsomal assays, respectively) and orally bioavailable (F = 12%) SCD inhibitor 11 . Replacement of the methoxy group of 11 by an ethylamino group afforded 12, which was more potent (SCD IC50 = 40 pM, human microsomal), had acceptable PK parameters (Clp = 1.26 L/h/kg, F = 27%, = 1.1 h, mouse) and good in vivo reduction of desaturase activity (ID50 = 0.8 and 2.0 mg/kg at 2-3 and 6-7 h respectively). Thiazole derivative 12 was efficacious in reducing the desaturation index in a dose-dependent fashion when administered qd for 7 days. No eye or skin abnormalities were reported in the study. This apparent success in separating in vivo efficacy and untoward skin and eye effects was attributed to the combination of the high potency and short half-life of 12 .
Perhaps in light of the mechanism-based side effects, the therapeutic potential of SCD inhibitors has not been fully evaluated. The possibility exists that at least some of the chronic effects of SCD inhibition might be prevented by coadministration of fish oils or potentially a Toll4 antagonist . However, coformulation of an SCD inhibitor with fish oil has not been reported. Another possibility is that SCD inhibitors with appropriate PK and tissue partitioning properties may limit mechanism-based side effects.
One small-molecule SCD inhibitor is believed to have entered clinical trials as a result of a partnership between Xenon Pharmaceuticals and Novartis. The structure has not been disclosed and the current clinical status is unknown.
A recent development in the field of SCD research is the growing evidence that SCD inhibitors have anticancer and antiproliferative effects. Cancer cells activate the biosynthesis of saturated and monounsaturated FAs in order to sustain an increasing demand for phospholipids with appropriate acyl composition during cell replication . SCD inhibitor CVT-11,127 (13, IC50 = 220 nM, rat microsomal assay; IC50 = 81 nM, human HEPG2 cells)  reduced cell proliferation in vitro in human lung carcinoma cells .
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