Metabolism, Excretion, and Pharmacokinetics of ((3,3-Difluoropyrrolidin-1-yl)((2<i>S</i>,4<i>S</i>)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone, a Dipeptidyl Peptidase Inhibitor, in Rat, Dog and Human

Sharma, Raman; Sun, Hao; Piotrowski, David W.; Ryder, Tim F.; Doran, Shawn D.; Dai, Haiqing; Prakash, Chandra

doi:10.1124/dmd.112.047316

Cited by 29 publications

(21 citation statements)

References 22 publications

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“…Molecular docking is a commonly used approach to elucidate the important interactions between substrates and active site residues of enzymes. 39,58,59 Aer modeling, the poses with the lowest binding energy were chosen for analysis. For CYP-mediated oxidative metabolism to take place, the site of metabolism should be in proximity to the heme iron with a favored binding angle (90 ) for electron transfer reactions to occur.…”

Section: Structure-based Modeling Of 8:2 Ftoh With Cyp2c19mentioning

confidence: 99%

Biotransformation of 8:2 fluorotelomer alcohol by recombinant human cytochrome P450s, human liver microsomes and human liver cytosol

Guo

Ren

2016

Environ. Sci.: Processes Impacts

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Environmental impactFluorotelomer alcohols (FTOHs) are the precursors of peruoroalkyl acids (PFAAs) which are now considered as global persistent organic pollutants and are therefore the potential source of PFAAs. CYP2C19 that we characterized plays a crucial role in the biotransformation of 8:2 FTOH in the human body to form a more toxic metabolite (8:2 uorotelomer aldehyde). Phase II metabolism (glucuronidation and sulfation) showed higher efficiency than phase I metabolism, which indicates that forming conjugates is the major fate of 8:2 FTOH metabolism. These results will help future epidemiological studies in the assessment of indirect sources of human exposure to PFAAs and potential health risks of uorotelomer alcohols.

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Section: Structure-based Modeling Of 8:2 Ftoh With Cyp2c19mentioning

confidence: 99%

Biotransformation of 8:2 fluorotelomer alcohol by recombinant human cytochrome P450s, human liver microsomes and human liver cytosol

Guo

Ren

2016

Environ. Sci.: Processes Impacts

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“…Although examples of metabolic cleavage of pyrimidine exist, it is an uncommon biotransformation pathway (Prakash and Cui, 1997;Sharma et al, 2012). Even more rarely observed has been recyclization after pyrimidine scission, which we found was described in only two other cases: (S)-25 and AZD3839 in rats (Lindgren et al, 2013) and vicriviroc in humans (Ghosal et al, 2007).…”

Section: Discussionmentioning

confidence: 55%

Elucidating the Mechanism of Cytochrome P450–Mediated Pyrimidine Ring Conversion to Pyrazole Metabolites with the BACE1 Inhibitor GNE-892 in Rats

Takahashi

Ma²,

Deese

et al. 2014

Drug Metab Dispos

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We investigated an uncommon biotransformation of pyrimidine during the metabolism of GNE-892 ((R)-2-amino-1,39,39-trimethyl-79-(pyrimidin-5-yl)-39,49-dihydro-29H-spiro[imidazole-4,19-naphthalen]-5(1H)-one), a b-secretase 1 inhibitor. Three novel metabolites, formed by conversion of pyrimidine to pyrazole, were observed in the 14 C-radiolabeled mass balance study in rats. Their structures were characterized by high-resolution mass spectrometry and nuclear magnetic resonance. Although these metabolites accounted for <5% of the administered dose, their unique nature prompted us to conduct further investigations. The pyrazolecontaining metabolites were formed in vitro with rat hepatocytes and liver microsomes, which supported that they were formed during hepatic metabolism. Further, their generation was inhibited by 1-aminobenzotriazole, indicating involvement of cytochrome P450s. Studies with rat recombinant enzymes identified that CYP2D2 generated the N-hydroxypyrazole metabolite from GNE-892. This biotransformation proceeded through multiple steps from the likely precursor, pyrimidine N-oxide. On the basis of these data, we propose a mechanism in which the pyrimidine is activated via N-oxidation, followed by a second oxidative process that opens the pyrimidine ring to form a formamide intermediate. After hydrolysis of the formamide, a carbon is lost as formic acid, together with ring closure to form the pyrazole ring. This article highlights a mechanistic approach for determining the biotransformation of the pyrimidine to a pyrazole for GNE-892.

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“…On the other hand, few cases of ring opening of pyridine have been reported, including microbial ring opening of pyridine derivatives (Kaiser et al, 1996), the formation of muconaldehyde from benzene mediated by cytochrome P450 (Latriano et al, 1986), and the formation of E-2-(acetaminomethylene) succinate from a vitamin B6 degradant (McCulloch et al, 2009). It is noteworthy that there are reports, albeit rare, on other six-membered aromatic heterocyclic ring-opening biotransformation, such as pyrimidine ring-cleaved metabolites of PF-00734200, a dipeptidyl peptidase inhibitor (Sharma et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Investigations into the Mechanisms of Pyridine Ring Cleavage in Vismodegib

Khojasteh

Qin

et al. 2014

Drug Metab Dispos

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Vismodegib (Erivedge, GDC-0449) is a first-in-class, orally administered small-molecule Hedgehog pathway inhibitor that is approved for the treatment of advanced basal cell carcinoma. Previously, we reported results from preclinical and clinical radiolabeled mass balance studies in which we determined that metabolism is the main route of vismodegib elimination. The metabolites of vismodegib are primarily the result of oxidation followed by glucuronidation. The focus of the current work is to probe the mechanisms of formation of three pyridine ring-cleaved metabolites of vismodegib, mainly M9, M13, and M18, using in vitro, ex vivo liver perfusion and in vivo rat studies. The use of stable-labeled ( 13 C 2 , 15 N)vismodegib on the pyridine ring exhibited that the loss of carbon observed in both M9 and M13 was from the C-6 position of pyridine. Interestingly, the source of the nitrogen atom in the amide of M9 was from the pyridine. Evidence for the formation of aldehyde intermediates was observed using trapping agents as well as 18 O-water. Finally, we conclude that cytochrome P450 is involved in the formation of M9, M13, and M18 and that M3 (the major mono-oxidative metabolite) is not the precursor for the formation of these cleaved products; rather, M18 is the primary cleaved metabolite.

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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

Cited by 29 publications

References 22 publications

Biotransformation of 8:2 fluorotelomer alcohol by recombinant human cytochrome P450s, human liver microsomes and human liver cytosol

Biotransformation of 8:2 fluorotelomer alcohol by recombinant human cytochrome P450s, human liver microsomes and human liver cytosol

Elucidating the Mechanism of Cytochrome P450–Mediated Pyrimidine Ring Conversion to Pyrazole Metabolites with the BACE1 Inhibitor GNE-892 in Rats

Investigations into the Mechanisms of Pyridine Ring Cleavage in Vismodegib

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