Saxagliptin

Fig. 2 Structure drawing of saxagliptin. Binding region of DPP-IV showing saxa-gliptin (ball-stick model) interactions with key amino acid residues (stick model) from X-ray crystal structure (3BJM) (produced with Pymol)...

Involvement of DPP-IV catalytic residues in enzyme-saxagliptin complex formation. Protein Sci 17(2) 240-250... 

USAN Saxagliptin Trade Name Onglyza Bristol-Myers Squibb Co. Launched 2009... 

Reductive amination was also conducted using cell extracts from E. coli strain SC16496 expressing PDHmod and cloned FDH from Pichia pastoris. Cells from a 15-L tank had 133 u/g FDH, 65u/g PDH (phenylpyruvate assay), and 12.7 u/g PDH (assayed with keto acid 3). The extract was used for conversion of 30g 3 to 4 in close to 100% yield, and this material, after filtration for protein removal, was converted to 2 by BOC protection. Further experiments showed that the E. coli extract could be used at 2.5% w/v concentration instead of the 12.5% concentration used for batches with Pichia pastoris extract. In subsequent experiments, the substrate input was increased to 100 g/ L and the reaction was carried out at pH 8.0. Cell extracts of E. coli strain SC16496 after polyethyleneamine treatment, clarification and concentration was used to complete the reaction in 30hrs with >96% yield and >99.9% ee of product 4. PDHmod and FDH expressed in E. coli have now been used to prepare several hundred kg of BOC-protected amino acid 2 to support the development of Saxagliptin (Hanson et al., 2007). 

Glucagon-like peptide-1 (GLP-1) agonists Liraglutide Saxagliptin... 

FIGURE 16.3 (A) Antidiabetic drug Saxagliptin 5. (B) Enzymatic reductive amination of... 

Reductive amination was also conducted using cell extracts from E. coli strain SC16496 expressing PDHmod and cloned FDH from Pichia pastoris. Cell extracts after polyethyleneamine treatment, clarification, and concentration were used to complete the reaction in 30 h with greater than 96% yield and more than 99.9% EE of product 7. This process has now been used to prepare several hundred kilograms of boc-protected amino acid 8 to support the development of Saxagliptin [40]. 

The synthesis of DPP-IV inhibitor Saxagliptin 5 also required (55)-5-amino-carbonyl-4,5-dihydro-lH-pyrrole-l-carboxylic acid, l-(l,l-dimethylethyl)ester 10 (Figure 16.3C). Direct chemical ammonolyses were hindered by the requirement for aggressive reaction conditions, which resulted in unacceptable levels of amide race-mization and side-product formation, while milder two-step hydrolysis-condensation protocols using coupling agents such as 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) [41] were compromised by reduced overall yields. To address this issue, a biocatalytic procedure was developed based on the Candida antartica lipase B (CALB)-mediated ammonolysis of (55)-4,5-dihydro-lH-pyrrole-l,5-dicarboxylic acid, l-(l,l-dimethylethyl)-5-ethyl ester 9 with ammonium carbamate to furnish 10 without racemization and with low levels of side-product formation. 

Augeri DJ, Robl JA, Betebenner DA, Magnin DR, et al. Discovery and preclinical profile of saxagliptin (BMS-477118) a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Journal of Medicinal Chemistry 48, 5025, 2005. 

Hanson RL, Goldberg SL, Brzozowski DB, et al. Preparation of an amino acid intermediate for the dipeptidyl peptidase IV inhibitor, saxagliptin, using a modified phenylalanine dehydrogenase. Advanced Synthesis and Catalysis 349(8-1-9), 1369, 2007. 

Gill I, Patel RN. Biocatalytic ammonolysis of (5S)-4,5-dihydro-lH-pyrrole-l,5-dicarboxylic acid, l-(l,l-dimethylethyl)-5-ethyl ester preparation of an intermediate to the dipeptidyl peptidase IV inhibitor saxagliptin. Bioorganic and Medicinal Chemistry Letters 16(3), 705, 2006. 

Keywords Incretiii, glucagon-Mke peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), entero-insular axis, exenatide, liraglutide, vildagliptin, sitagliptin, saxagliptin, DPP-4. 

Saxagliptin (2009) http //www.fda.gov/ohrms/dockets/ac/09/brie ng/2009-4422bl-01-FDA.pdf. 

In a review of studies adverse reactions to saxagliptin were similar to those reported with sitagliptin [31 ]. Headache, nasopharyngitis, upper respiratory tract infections, and urinary tract infections were reported in more than 5% of patients taking saxagliptin 2.5 mg/day and 5 mg/day. 

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