Gosogliptin (PF-00734200)

An inhibitor of DPP-4

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库存: 现货

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1mg

￥3225.00

2580.00

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5mg

￥6412.00

5130.00

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10mg

￥10912.00

8730.00

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20mg

￥19062.00

15250.00

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货号: ajce47168
CAS: 869490-23-3
别名: (3,3-二氟吡咯烷-1-基)[(2S,4S)-4-[4-(嘧啶-2-基)哌嗪-1-基]吡咯烷-2-基]甲酮,PF-00734200; PF-734200
分子式: C17H24F2N6O
分子量: 366.41
纯度: >98%
溶解度: Soluble in DMSO
储存: Store at -20°C
库存: 现货

Background

Gosogliptin is an inhibitor of dipeptidyl peptidase 4 (DPP-4; IC₅₀ = 0.013 ?M).¹ It is selective for DPP-4 over DPP-2, -3, -8, and -9 (IC₅₀s = 3.3, >30, 7, and 5.98 ?M, respectively), the serine proteases APP, FAP, and POP (IC₅₀s = >30, 10.3, and >30 ?M, respectively), and a panel of enzymes, receptors, and ion channels (IC₅₀s = >10 ?M for all).

1.Ammirati, M.J., Andrews, K.M., Boyer, D.D., et al.(3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: A potent, selective, orally active dipeptidyl peptidase IV inhibitorBioorg. Med. Chem. Lett.19(7)1991-1995(2009)

Protocol

Kinase experiment:

Studies to identify the P450 isoform(s) responsible for formation of M5 are conducted using chemical inhibition and incubation in recombinant P450 isozymes. Inhibition studies are performed with each of the following inhibitors: Furafylline (10 μM for CYP1A2), Sulfaphenazole (10 μM for CYP2C9), Quinidine (10 μM for CYP2D6), (+)N-3-benzylnirvanol (10 μM for CYP2C19), and Ketoconazole (1 μM for CYP3A4). Incubations (1 ml) are performed in duplicate with NADPH (1.3 mM) in 1.5 mL plastic Eppendorf tubes open to air at 37°C in a shaking water bath. Samples are preincubated at 37°C for 5 min before the addition of NADPH. Each incubation contains microsomes (2 mg/mL protein), 100 mM potassium phosphate buffer (pH 7.4), 10 mM MgCl2, 10 μM Gosogliptin (PF-00734200), and one of the above inhibitors. A control sample is also prepared without inhibitor. Additional controls using marker substrates (each at 10 μM), in the presence and absence of P450-specific inhibitors, are used to confirm inhibition results and included Phenacetin (CYP1A2), Tolbutamide (CYP2C9), (S)-Mephenytoin (CYP2C19), Dextromethorphan (CYP2D6), and Testosterone (CYP3A4). At 0 and 30 min, incubations are quenched with an equal volume of ice-cold acetonitrile. Samples are then placed on ice for 15 min to allow precipitation of protein and subsequently centrifuged at 1800g for 5 min. An aliquot is removed from each sample and injected onto the HPLC/MS system[2].

Animal experiment:

Rats[2] A group of SD rats (n=3/gender) is administered a single 5 mg/kg oral dose of [14C] Gosogliptin for the mass balance study. For biliary excretion experiments, another group of two male and two female bile duct-cannulated rats is administered a single 5 mg/kg oral dose of [14C] Gosogliptin in similar fashion. The dose is formulated as a suspension in 0.5% methyl cellulose on the day before dose administration. Each rat received an approximate dose of ～60 μCi of radiolabeled material. Urine and feces are collected from intact animals for 7 days at 0 to 8, 8 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144- to 168-h intervals after the dose. The first feces sample is collected at 0 to 24 h after the dose. Bile and urine samples are collected from bile duct-cannulated animals at 0- to 8-, 8- to 24-, and 24- to 48-h intervals after the dose. The volumes of urine and bile samples are recorded, and all of the biological samples are stored at -20°C until analysis. For determination of pharmacokinetic parameters and identification of circulating metabolites, a third group of jugular vein-cannulated rats (n=10/gender) is given an oral dose of 5 mg/kg [14C] Gosogliptin. Blood from two animals per gender is collected at 0.5, 1, 2, 4, and 8 h postdose in heparinized (lithium heparin anticoagulant) tubes. The blood samples are centrifuged at 1000g for 10 min to obtain the plasma. Plasma is transferred to clean tubes and stored at -20°C until analysis.

参考文献:

[1]. Dai H, et al. The pharmacokinetics of PF-734200, a DPP-IV inhibitor, in subjects with renal insufficiency. Br J Clin Pharmacol. 2011 Jul;72(1):85-91.
[2]. Sharma R, et al. Metabolism, excretion, and pharmacokinetics of ((3,3-difluoropyrrolidin-1-yl)((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone, a dipeptidyl peptidase inhibitor, in rat, dog and human. Drug Metab Dispos. 2012 Nov;40(11):2143-61.