Carbon‐14 labeling of Saxagliptin (BMS‐477118)

Cao, Kai; Bonacorsi, Samuel J.; Balasubramanian, Balu; Hanson, Ronald L.; Manchand, Percy S.; Godfrey, Jollie D.; Fox, Rita; Christopher, Lisa J.; Su, Hong; Iyer, Ramaswamy A.

doi:10.1002/jlcr.1450

Cited by 12 publications

(14 citation statements)

References 19 publications

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“…1) and stable-labeled (Cao et al, 2007). Unlabeled saxagliptin (P, (1S,3S,5S)-2-((S)-2-amino-2-(-3-hydroxyadamantan-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile); and reference standards for 5-hydroxy saxagliptin, (M2, (1S,3S,5S)-2-((S)-2-amino-2-((1r,3R,5S,7S)-3,5-dihydroxyadamantan-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile); degradant (D1, (1aS,4S,6aR,7aS)-4-(-3-hydroxyadamantan-1-yl)-6-iminohexahydro-1H-cyclopropa [4,5]pyrrolo[1,2-a]pyrazin-3(1aH)-one); the S,R,S,S and S,S,S,R diastereomers of saxagliptin (Supplemental Fig.…”

Section: Chemicals [mentioning

confidence: 99%

Characterization of the In Vitro and In Vivo Metabolism and Disposition and Cytochrome P450 Inhibition/Induction Profile of Saxagliptin in Human

Boulton²,

Barros³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Saxagliptin is a potent dipeptidyl peptidase-4 inhibitor approved for the treatment of type 2 diabetes mellitus. The pharmacokinetics and disposition of [ 14 C]saxagliptin were investigated in healthy male subjects after a single 50-mg (91.5 Ci) oral dose. Saxagliptin was rapidly absorbed (T max , 0.5 h). Unchanged saxagliptin and 5-hydroxy saxagliptin (M2), a major, active metabolite, were the prominent drug-related components in the plasma, together accounting for most of the circulating radioactivity. Approximately 97% of the administered radioactivity was recovered in the excreta within 7 days postdose, of which 74.9% was eliminated in the urine and 22.1% was excreted in the feces. The parent compound and M2 represented 24.0 and 44.1%, respectively, of the radioactivity recovered in the urine and feces combined. Taken together, the excretion data suggest that saxagliptin was well absorbed and was subsequently cleared by both urinary excretion and metabolism; the formation of M2 was the major metabolic pathway. Additional minor metabolic pathways included hydroxylation at other positions and glucuronide or sulfate conjugation. Cytochrome P450 (P450) enzymes CYP3A4 and CYP3A5 metabolized saxagliptin and formed M2. Kinetic experiments indicated that the catalytic efficiency (V max /K m ) for CYP3A4 was approximately 4-fold higher than that for CYP3A5. Therefore, it is unlikely that variability in expression levels of CYP3A5 due to genetic polymorphism will impact clearance of saxagliptin. Saxagliptin and M2 each showed little potential to inhibit or induce important P450 enzymes, suggesting that saxagliptin is unlikely to affect the metabolic clearance of coadministered drugs that are substrates for these enzymes.

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Section: Chemicals [mentioning

confidence: 99%

Characterization of the In Vitro and In Vivo Metabolism and Disposition and Cytochrome P450 Inhibition/Induction Profile of Saxagliptin in Human

Boulton²,

Barros³

et al. 2012

Drug Metab Dispos

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“…The synthetic utility of carbon‐14 labeled methyl 2‐chloro‐2‐oxoacetate ( [ 14 C]‐1 ) and carbon‐14 labeled ethyl 2‐chloro‐2‐oxoacetate as a carbon‐14 labeled oxalyl chloride equivalent has been demonstrated on several occasions in our lab 24. One example showing the synthesis of a carbon‐14 labeled dichloropyrazinone ( [ 14 C]‐7 ) is highlighted in Scheme .…”

Section: Resultsmentioning

confidence: 99%

Carbon‐14 labeled methyl 2‐chloro‐2‐oxoacetate: a convenient carbon‐14 labeled oxalyl chloride equivalent

Burrell

Easter

Bonacorsi

et al. 2009

Labelled Comp Radiopharmac

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Oxalyl chloride is a versatile two‐carbon building block for synthesizing organic molecules. Carbon‐14 labeled oxalyl chloride should be a useful reagent for labeling many of these compounds. Unfortunately, its preparation suffers from low radiochemical yield and problems with stability, isolation and analysis. Because of these issues, the reagent is not a convenient or practical carbon‐14 label source. Synthetically, methyl 2‐chloro‐2‐oxoacetate reacts as an oxalyl chloride equivalent. This report describes a reliable and efficient two‐step synthesis of carbon‐14 labeled methyl 2‐chloro‐2‐oxoacetate ([14C]‐1) from readily available carbon‐14 labeled dimethyl oxalate ([14C]‐2). The labeled oxalate was first treated with aqueous base to give the mono‐potassium salt of 2‐methoxy‐2‐oxoacetate ([14C]‐3), which was then reacted with oxalyl chloride to give [14C]‐1 as a solution in dichloromethane. The overall radiochemical yield for this process was essentially quantitative, and [14C]‐1 was found to be stable and easy to use in further synthetic manipulations. Copyright © 2009 John Wiley & Sons, Ltd.

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“…The amide coupling reaction to form compound ( 12 ) followed by deprotection to form compound ( 14 ) was performed in a similar way as described by K. Cao . To a 10‐mL vial equipped with a stir bar containing crude 14 (74.3 mg, 0.21 mmol) dissolved in 2‐propanol (0.076 mL) was added 1:1 dichloromethane:water (4 mL).…”

Section: Synthesismentioning

confidence: 99%

“…Prepared in the same way as that described by K. Cao, 70% yield. 1 H NMR (400 MHz, DMSO‐ d 6 ) δ 6.88 (d, J = 8.5 Hz, 1H), 5.13 (d, J = 10.3 Hz, 1H), 4.42 (s, 1H), 4.33 (d, J = 9.0 Hz, 1H), 3.84 (d, J = 6.5 Hz, 1H), 2.18 (d, J = 13.8 Hz, 1H), 2.13–2.06 (m, 3H), 1.87 (t, J = 5.9 Hz, 1H), 1.66–1.30 (m, 21H).…”

Section: Synthesismentioning

confidence: 99%

“…14 C‐labeled saxagliptin ( 1 ), 13 CD 2 ‐labeled saxagliptin ( 2 ), and its 13 CD 2 ‐labeled 5‐hydroxy metabolite ( 3 ) were synthesized to further support development of the compound for use in key biological studies. The synthesis of 14 C‐labeled saxagliptin has previously been reported by K. Cao . Cao's initial syntheses utilized [ 14 C]potassium cyanide (Scheme , Route 1) or ethyl[1,2‐ 14 C]oxalyl chloride (Route 2) as the labeled reagents followed by several linear steps.…”

Section: Introductionmentioning

confidence: 99%

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The synthesis of¹⁴C-labeled,¹³CD₂-labeled saxagliptin, and its¹³CD₂-labeled 5-hydroxy metabolite

Tran

Maxwell

Cao

et al. 2014

J. Label Compd. Radiopharm

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(14)C-labeled saxagliptin, (13) CD2-labeled saxagliptin, and its (13) CD2-labeled 5-hydroxy metabolite were synthesized to further support development of the compound for biological studies. This paper describes new syntheses leading to the desired compounds. A total of 3.0 mCi of (14)C-labeled saxagliptin was obtained with a specific activity of 53.98 μCi/mg (17.13 mCi/mmol). The radiochemical purity determined by HPLC was 99.29%, and the overall radiochemical yield was 3.0% based upon 100 mCi of [(14)C]CH2 I2 starting material. By following similar synthetic routes, 580.0 mg of (13)CD2-labeled saxagliptin and 153.1 mg of (13)CD2-labeled 5-hydroxysaxagliptin metabolite were prepared.

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Carbon‐14 labeling of Saxagliptin (BMS‐477118)

Abstract: BMS-477118 in a short sequence.

Cited by 12 publications

References 19 publications

Characterization of the In Vitro and In Vivo Metabolism and Disposition and Cytochrome P450 Inhibition/Induction Profile of Saxagliptin in Human

Characterization of the In Vitro and In Vivo Metabolism and Disposition and Cytochrome P450 Inhibition/Induction Profile of Saxagliptin in Human

Carbon‐14 labeled methyl 2‐chloro‐2‐oxoacetate: a convenient carbon‐14 labeled oxalyl chloride equivalent

The synthesis of¹⁴C-labeled,¹³CD₂-labeled saxagliptin, and its¹³CD₂-labeled 5-hydroxy metabolite

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Carbon‐14 labeling of Saxagliptin (BMS‐477118)

Abstract: BMS-477118 in a short sequence.

Cited by 12 publications

References 19 publications

Characterization of the In Vitro and In Vivo Metabolism and Disposition and Cytochrome P450 Inhibition/Induction Profile of Saxagliptin in Human

Characterization of the In Vitro and In Vivo Metabolism and Disposition and Cytochrome P450 Inhibition/Induction Profile of Saxagliptin in Human

Carbon‐14 labeled methyl 2‐chloro‐2‐oxoacetate: a convenient carbon‐14 labeled oxalyl chloride equivalent

The synthesis of14C-labeled,13CD2-labeled saxagliptin, and its13CD2-labeled 5-hydroxy metabolite

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The synthesis of¹⁴C-labeled,¹³CD₂-labeled saxagliptin, and its¹³CD₂-labeled 5-hydroxy metabolite