Orally bioavailable,liver-selective stearoyl-CoA desaturase (SCD) inhibitors

We discovered a structurally novel SCD (Δ9 desaturase) inhibitor 4a (CVT-11,563) that has 119 nM potency in a human cell-based (HEPG2) SCD assay and selectivity against Δ5 and Δ6 desaturases. This compound has 90% oral bioavailability (rat) and excellent plasma exposure (dAUC 935 ng h/mL). Additionally, 4a shows moderately selective liver distribution (three times vs plasma and adipose tissue) and relatively low brain penetration. In a five-day study (high sucrose diet, rat) compound 4a significantly reduced SCD activity as determined by GC analysis of fatty acid composition in plasma and liver. We describe the discovery of 4a from HTS hit 1 followed by scaffold replacement and SAR studies focused on DMPK properties.     

Discovery of liver-targeted inhibitors of stearoyl-CoA desaturase (SCD1)

Inhibitors based on a benzo-fused spirocyclic oxazepine scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles. Responding to concerns about target localization and potential mechanism-based side effects, an initial effort was also made to improve liver concentration in an available rat PK model. An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies.     

Conversion of systemically-distributed triazole-based stearoyl-CoA desaturase (SCD) uHTS hits into liver-targeted SCD inhibitors

It has been demonstrated that once-a-day dosing of systemically-distributed SCD inhibitors leads to adverse events in eye and skin. Herein, we describe our efforts to convert a novel class of systemically-distributed potent triazole-based uHTS hits into liver-targeted SCD inhibitors as a means to circumvent chronic toxicity.     

Potent,orally bioavailable,liver-selective stearoyl-CoA desaturase (SCD) inhibitors

Two structurally distinct series of SCD (Δ9 desaturase) inhibitors (1 and 2) have been previously reported by our group. In the present work, we merged the structural features of the two series. This led to the discovery of compound 5b (CVT-12,012) which is highly potent in a human cell-based (HEPG2) SCD assay (IC₅₀ = 6 nM). This compound has 78% oral bioavailability in rats and is preferentially distributed into liver (76 times vs plasma) with relatively low brain penetration. In a five-day study (sucrose fed rats) compound 5b significantly reduced SCD activity in a dose-dependent manner as determined by GC analysis of fatty acid composition in plasma and liver, and significantly reduced liver triglycerides versus the control group (～50%).     

Discovery of potent and liver-targeted stearoyl-CoA desaturase (SCD) inhibitors in a bispyrrolidine series

Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.     

Discovery of potent and liver-selective stearoyl-CoA desaturase (SCD) inhibitors in an acyclic linker series

Elevated levels of stearoyl-CoA desaturase (SCD) activity have been implicated in metabolic disorders such as obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed inhibitors, our research efforts have been focused on the search for new liver-targeting compounds. This work has led to the discovery of novel, potent and liver-selective acyclic linker SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.     

Novel,potent, selective,and metabolically stable stearoyl-CoA desaturase (SCD) inhibitors

We identified a series of structurally novel SCD (Δ9 desaturase) inhibitors via high-throughput screening and follow-up SAR studies. Modification of the central bicyclic scaffold has proven key to our potency optimization effort. The most potent analog (8g) had IC₅₀ value of 50 pM in a HEPG2 SCD assay and has been shown to be metabolically stable and selective against Δ5 and Δ6 desaturases.     

Single nucleotide polymorphisms in the open reading frame of the stearoyl-CoA desaturase gene and resulting genetic variants in Canadian Holstein and Jersey cows.

Stearoyl-CoA desaturase (SCD) catalyzes the synthesis of conjugated linoleic acid (CLA) and mono-unsaturated fatty acids (MUFA) from their saturated counterparts in the mammary gland and adipose tissue of ruminant animals. We hypothesize that single nucleotide polymorphisms (SNPs) in the SCD gene account for some of the differences in SCD activity, and consequently for some of the variations in CLA and MUFA content of milk fat between Holsteins and Jersey cows and within these two breeds. We analyzed the open reading frame of the SCD gene of 44 Holsteins and 48 Jerseys for SNPs by sequencing. Three SNPs: 702A --> G, 762T --> C and 878C --> T were identified in both breeds and a further SNP, 435G --> A, was unique to Holsteins. The SNPs characterized four different genetic variants in Holsteins: A (G(435)A(702)T(762)C(878)), A1 (A(435)A(702)T(762)C(878)), B (G(435)G(702)C(762)T(878)) and B1 (A(435)G(702)C(762)T(878)), with only variants A and B in Jerseys. SNP 878C --> T resulted in a non-synonymous codon change while the rest resulted in synonymous codon changes giving rise to two protein variants, A having alanine and B having valine. Allele A was the most prevalent in the two breeds. These differences may, therefore, contribute to existing variations in CLA and fat content between and within Canadian Holstein and Jersey cows.     

Benzimidazole-carboxamides as potent and bioavailable stearoyl-CoA desaturase (SCD1) inhibitors from ligand-based virtual screening and chemical optimization

The discovery of potent benzimidazole stearoyl-CoA desaturase (SCD1) inhibitors by ligand-based virtual screening is described. ROCS 3D-searching gave a favorable chemical motif that was subsequently optimized to arrive at a chemical series of potent and promising SCD1 inhibitors. In particular, compound SAR224 was selected for further pharmacological profiling based on favorable in vitro data. After oral administration to male ZDF rats, this compound significantly decreased the serum fatty acid desaturation index, thus providing conclusive evidence for SCD1 inhibition in vivo by SAR224.     

Association analyses of single nucleotide polymorphisms in bovine stearoyl-CoA desaturase and fatty acid synthase genes with fatty acid composition in commercial cross-bred beef steers

Two previously reported non‐synonymous coding single nucleotide polymorphisms (SNPs) of bovine stearoyl‐CoA desaturase (delta‐9‐desaturase) (SCD) (c.878C>T) and fatty acid synthase (FASN) (g:17924A>G) were assessed for their associations with 72 individual and 12 groups of fatty acids in brisket adipose tissue of 223 Canadian commercial cross‐bred beef steers. It was found that the ‘CC’ genotype of the SCD SNP was significantly associated with lower concentrations of saturated fatty acids (SFA) including 10:0, 14:0 and 20:0, higher concentrations of monounsaturated fatty acids including 9c‐14:1, 12c‐16:1 and 13c‐18:1, higher concentrations of polyunsaturated fatty acids (PUFA) including 9c,15c‐18:2, 10c,12c‐18:2, 11c,13t‐18:2 and 12c,14t‐18:2, but lower concentrations of other PUFA of 9c,13t/8t,12c and 20:2n‐6 (P < 0.05). The ‘AA’ genotype of the FASN SNP was significantly associated with higher concentrations of SFAs of 10:0, 12:0, 13:0, 14:0 and 15:0, lower concentrations of unsaturated fatty acids of 9c‐18:1 and 20:3n‐6, and higher concentrations of unsaturated fatty acids of 9c‐14:1 and 12c‐16:1 (P < 0.05). Significant epistatic effects between the SCD and FASN SNP genotypes were also found for several fatty acids including 10:0, 23:0, 6t/7t/8t‐18:1, 12t‐18:1, 13t/14t‐18:1, 16t‐18:1, total trans18:1 and 9c,13t/8t,12c‐18:2 (P < 0.05). These results further suggest that SCD and FASN are strong candidate genes influencing fatty acid composition in beef cattle.     

Novel SNPs in the caprine stearoyl-CoA desaturase (SCD) and decorin (DCN) genes that are associated with growth traits in Chinese goat breeds

Stearoyl-CoA desaturase (SCD) is an iron-containing enzyme involving in the biosynthesis of monounsaturated fatty acids (MUFA) in mammary gland and adipose tissue, while decorin (DCN) consists of a protein core and a single dermatan or chondroitin sulfate glycosaminoglycan chain, contributing multifunctionally to matrix assembly, modulation of the activity of growth factors and cell migration and proliferation. However, few studies have focused on the genetic variability of them in goat. Herein, five Chinese goat breeds (1229 animals) were analyzed. Based on DNA pooling and PCR-RFLP, three nucleotide substitutions, one of which caused a amino acid substitution, were detected in SCD gene and three haploids (A, B, C) were constructed. According to SSCP analysis and DNA sequencing methods, a 2-bp deletion and two other SNPs were found existing in another analyzed gene DCN, and three haploids (X, Y, Z) were built. Associations between the genotypes and the growth traits (body length, body height, chest circumference, cannon circumference) were also analyzed. For SCD gene, genotype CC individuals had significant greater body height in Guanzhong and body length in both Guanzhong and Xinong saanen than genotype BC individuals (P < 0.05). For DCN gene, individuals with genotype XX was obviously higher than that with genotype XY (P < 0.05). These results indicated that genotype CC of SCD gene and genotype XX of DCN gene could be used for the breeding of new breeds of goat in China.