Saxagliptin

Saxagliptin Chemische Eigenschaften,Einsatz,Produktion Methoden

• Chemische Eigenschaften

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• Verwenden

  Saxagliptin is a potent and selective reversible inhibitor of dipeptidyl peptidase-4, which is being developed for the treatment of type 2 diabetes. It is absorbed rapidly after oral administration and has a pharmacokinetic profile compatible with once daily dosing.

• Definition

  ChEBI: A monocarboxylic acid amide obtained by formal condensation of the carboxy group of (2S)-amino(3-hydroxyadamantan-1-yl)acetic acid with the amino group of (1S,3S,5S)-2-azabicyclo[3.1.0]hex ne-3-carbonitrile. Used in its monohydrate form for the treatment of Type II diabetes.

• Clinical Use

  Saxagliptin, previously identified as BMS-477118, is an oral hypoglycemic of the dipeptidyl peptidase-4 (DPP-4) inhibitor class developed by Bristol-Myers Squibb for the treatment of type 2 diabetes. DPP-IV is the primary enzyme responsible for degradation of incretins, such as glucagon-like peptide-1 (GLP-1), which is a hormone responsible for the glucose-dependent stimulation of insulin in humans. Inhibitors of DPP-IV serve as effective glucose regulators by increasing the endogenous concentration of GLP-1.

• Synthese

  The initial discovery route to saxagliptin was a 15-step, convergent synthesis focused on the production and use of compounds 109 and 113 (Schemes a and b). While the strategy of early drug delivery involved rapid synthesis to support preclinical activities and Phase I clinical trials, as saxagliptin entered Phase II, a greater emphasis was placed on defining and demonstrating a commercially viable synthetic process. Scheme a describes a more expedient route to the preparation of adamantylamino acid 109. Commercially available 1-adamantoic acid (106) was first converted to the corresponding acid halide through the use of thionyl chloride prior to a Grignard addition reaction utilizing iodomethane and magnesium metal to furnish ketone 107. This ketone was then subjected to oxidizing conditions involving potassium permanganate to provide the hydroxylated ketoacid 108. The amino acid 109 was furnished through the use of phenylalanine dehydrogenase in near-quantitative yield in 99% enantioselectivity.
  The synthesis of 113 began with commercially available ethyl N-tert-butoxycarbonylpyroglutamate (110) (Scheme b). Selective reduction of the amide carbonyl within 110 through the use of lithium triethylborohydride followed by acylation and baseinduced elimination of the resulting aminal and careful hydrolysis gave rise to dihydropyrrole 111 with full retention of stereochemical configuration in 95% yield. Amidation followed by Simmons¨C Smith cyclopropanation employing methylene iodide converted 111 to the cyclopropanated product 112, which was then converted to the key coupling partner 113.
  The core of saxagliptin was formed by the amide coupling of amino acid 109 and methanoprolinamide 113 to give amide 114 in 95% yield (Scheme c). Subsequent dehydration of the primary amide 114 using trifluoroacetic acid anhydride and ethyl nicotinate gave nitrile 115 in 98% yield. Removal of both the alcohol and amine protecting groups with HCl afforded saxagliptin (XVIII) in 88% yield.

  

• Stoffwechsel

  Metabolism is mainly by cytochrome P450 3A4/5. The major metabolite of saxagliptin is also a selective, reversible, competitive DPP 4 inhibitor, half as potent as saxagliptin.
  Saxagliptin and 5-hydroxy saxagliptin are excreted in the urine; there may be some active renal excretion of unchanged saxagliptin. There is also some elimination via the faeces.

Saxagliptin Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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