945667-22-1

While liraglutide targets the incretin system as a GLP-1 analog for therapeutic intervention in T2DM, saxagliptin enhances GLP-1 plasma concentrations by inhibiting the DPP-4 enzyme responsible for degradation of GLP-1 by cleavage of the two N-terminal amino acids adjacent to alanine (or proline), thereby rendering the hormone inactive. Similarto vildagliptin, saxagliptin is a cyanopyrrolidine substrate-based inhibitor. The proline mimetic occupies the small S1-pocket while the nitrile’s trajectory aligns with the scissile bond of the substrate. The slow dissociation kinetics of saxagliptin is attributed to a reversible, covalent reaction between the nitrile and the catalytically active serine hydroxyl (Ser630). The steric bulk provided by the adamantyl moiety and the constrained cyclopropyl ring stabilizes the trans-rotamer of the amide, thereby preventing the problematic intramolecular cyclization, via the amino group attacking the nitrile, which is favored in the cis-conformation.
Since metabolism of saxagliptin is primarily mediated by CYP3A4/5, there is a potential for drug interactions with concomitant administration of strong inducers or inhibitors of these cytochrome P450 enzymes. The most common adverse events (>5% of patients) included upper respiratory tract infection, urinary tract infection, and headache.

Bristol-Myers-Squibb (US)

Saxagliptin Hydrate is a selective and reversible dipeptidyl peptidase-4 (DPP4) inhibitor that may be used to develop treatment for type 2 diabetes.

ChEBI: A hydrate that is the monohydrate form of anhydrous saxagliptin. Used for the treatment of Type II diabetes.

Onglyza

Saxagliptin (BMS-477118) is an orally active, highly potent and long-acting dipeptidyl peptidase IV inhibitor (human DPP-IV Ki = 0.9 nM; plasma DDP-IV inhibition = 87% 0.5-4h post 4 μmol/kg po. in normal rats) with therapeutic efficacy against type 2 diabetes in vivo (plasma glucose clearance = 28/43/61% post 0.3/1.0/3.0 μmol/kg po. in Zucker fa/fa rats).

The synthesis of (1S,3S,5S)-2-[(1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl]-1-(3-hydroxytricyclo[3.3.1.13,7]decan-1-yl)-2-oxoethyl]carbamic acid 1,1-dimethylethyl ester was carried out using (1S,3S,5S)-2-((2S)-2-amino-2- (3-hydroxyadamantan-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile monohydrate was carried out in the following general steps: 300 g (0.723 mol, 90.6% purity) of Boc-protected saxagliptin IA was added to a 12L three-necked flask equipped with a mechanical stirrer, a temperature probe and a nitrogen inlet. Dichloromethane (3L) and methanol (288 ml, 7.23 mol) and 36% hydrochloric acid (288 ml, 3.5 mol, 4.8 equiv) were added. The reaction mixture was stirred for 18 h until the reaction was complete (Boc-protected saxagliptin concentration in dichloromethane < 1 mg/ml as monitored by HPLC). After the reaction the mixture was divided into two phases, the upper aqueous phase was separated and collected (the lower dichloromethane phase was discarded). To the recovered aqueous phase, dichloromethane (6 L) and water (720 ml) were added, and then the pH was adjusted to 9.0-10.5 by slow dropwise addition of 5N NaOH solution (~600 ml). solid sodium chloride (120 g) was added and stirring was continued for 20 min. After phase separation, the lower dichloromethane phase was collected (the upper aqueous phase was discarded). The dichloromethane phase was washed with 1% aqueous ammonium chloride solution (450 ml), and after separation again, the lower dichloromethane phase was collected (the upper aqueous phase was discarded, pH=7.8). Dichloromethane was removed by adding about 4 L of ethyl acetate while distilling under reduced pressure at 25 °C and 50 mmHg until the final volume was reduced to 2.5 L when distillation was stopped. The remaining liquid was polished and filtered to remove solid sodium chloride. Concentration was continued until about 1 Kg (about 170 g of saxagliptin free base) was dissolved in 1 L of ethyl acetate. Water (17 ml) was added slowly and stirring was maintained for 10 minutes after crystallization was observed. Another 17 ml of water was added and stirring of the slurry was continued for 30 minutes. The solid was collected by filtration and the filter cake was washed with ethyl acetate (150 ml). The washed filter cake was dried under vacuum at room temperature to give 186 g of saxagliptin free base monohydrate (crystalline form H-1) in 81% yield.

Saxagliptin hydrochloride is supplied as a crystalline solid. A stock solution may be made by dissolving the saxagliptin (hydrochloride)in the solvent of choice,which should be purged with an inert gas. Saxagliptin hydrochloride is soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide (DMF). The solubility of saxagliptin hydrochloride in these solvents is approximately 10 mg/ml in ethanol and 20 mg/ml in DMSO and DMF. Further dilutions of the stock solution into aqueous buffers or isotonic saline should be made prior to performing biological experiments. Ensure that the residual amount of organic solvent is insignificant, since organic solvents may have physiological effects at low concentrations. Organic solvent-free aqueous solutions of saxagliptin(hydrochloride)can be prepared by directly dissolving the crystalline solid in aqueous buffers. The solubility of saxagliptin (hydrochloride)in PBS(pH 7.2), is approximately 2 mg/ml. We do not recommend storing the aqueous solution for more than one day.

[1] Patent: WO2008/131149, 2008, A2. Location in patent: Page/Page column 27-28
[2] Patent: WO2008/131149, 2008, A2. Location in patent: Page/Page column 26-27
[3] Patent: WO2008/131149, 2008, A2. Location in patent: Page/Page column 28