Enzymatic<i>C</i>-Demethylation of 1-[2-(5-<i>tert</i>-Butyl-[1,3,4] oxadiazole-2-carbonyl)-4-fluoro-pyrrolidin-1-yl]-2-(2-hydroxy-1,1-dimethyl-ethylamino)-ethanone (LC15-0133) in Rat Liver Microsomes

Yoo, Hye Hyun; Chung, Hye Jin; Lee, Jaeick; Lee, Chang-Suck; Kang, Min Jung; Kim, Dong-Hyun

doi:10.1124/dmd.107.019133

Cited by 13 publications

(9 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6) to form 2␣-dehydroxymethyl products (M6, -8, -10, -13, -18, and -19). Such nonenzymatic decarboxylation was also observed in the carboxyl metabolite of compound LC15-0133 while treated with rat liver microsomes (Yoo et al, 2008). The third one is lactonization of the carboxylic acid and the alcoholic groups to form the 12,14-lactone (M11) from intermediate B and the 14,12-lactone (M4) from intermediate C (Fig.…”

Section: Discussionmentioning

confidence: 90%

Metabolism of (2S)-Pterosin A: Identification of the Phase I and Phase II Metabolites in Rat Urine

Lee¹,

Hsu²,

Kang³

et al. 2012

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:The metabolic profile of the potent hypoglycemic agent, (2S)-pterosin A (1), in rat urine via intragastrical oral administration was investigated. In total, 19 metabolites (M1-M19) were identified. Among these, 16 metabolites were characterized by high-performance liquid chromatography solid-phase extraction-tube transfer-NMR, and seven metabolites were further isolated from the treated urine to enable further structural determination. Twelve of these are new compounds. The phase I metabolites of 1 were formed via various oxidations at positions C-3, C-10, C-12, C-13, or C-1 followed by decarboxylation of C-10 or C-14, and lactonization at C-12/C-14 or C-14/C-12. The phase II metabolites were glucuronide conjugates from the parent compound or phase I metabolites. The major metabolites were found to be (2S)-14-O-glucuronylpterosin A (M9), (2S)-2-hydroxymethylpterosin E (M14), and (؎)-pterosin B (M19). Quantitative HPLC analysis of metabolites, based on similar UV absorption and use of the regression equation of 1, indicated that ϳ71% 1 was excreted as metabolites in rat urine.

show abstract

Section: Discussionmentioning

confidence: 90%

Metabolism of (2S)-Pterosin A: Identification of the Phase I and Phase II Metabolites in Rat Urine

Lee¹,

Hsu²,

Kang³

et al. 2012

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…Another example of nonenzymatic decarboxylation of a carboxylic acid metabolite was described for LC15-0133 (1-[2-(5-tert-butyl-[1,3,4] oxadiazole-2-carbonyl)-4-fluoro-pyrrolidin-1-yl]-2-(2-hydroxy-1,1-dimethylethylamino)-ethanone), a t-butyl oxadiazole-containing compound previously in development for treatment of diabetes, using in vitro liver metabolism systems (Yoo et al, 2008). When incubated with D 2 O, the uptake of deuterium occurred on the resulting isopropyl methine carbon in rat liver microsomes.…”

Section: Discussionmentioning

confidence: 99%

Metabolism and Disposition of Oral Dabrafenib in Cancer Patients: Proposed Participation of Aryl Nitrogen in Carbon-Carbon Bond Cleavage via Decarboxylation following Enzymatic Oxidation

et al. 2013

View full text Add to dashboard Cite

A phase I study was conducted to assess the metabolism and excretion of [ 14 C]dabrafenib (GSK2118436; N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt), a BRAF inhibitor, in four patients with BRAF V600 mutation-positive tumors after a single oral dose of 95 mg (80 mCi). Assessments included the following: 1) plasma concentrations of dabrafenib and metabolites using validated ultra-highperformance liquid chromatography-tandem mass spectrometry methods, 2) plasma and blood radioactivity, 3) urinary and fecal radioactivity, and 4) metabolite profiling. Results showed the mean total recovery of radioactivity was 93.8%, with the majority recovered in feces (71.1% of administered dose). Urinary excretion accounted for 22.7% of the dose, with no detection of parent drug in urine. Dabrafenib is metabolized primarily via oxidation of the t-butyl group to form hydroxy-dabrafenib. Hydroxy-dabrafenib undergoes further oxidation to carboxy-dabrafenib, which subsequently converts to desmethyl-dabrafenib via a pH-dependent decarboxylation. The half-lives for carboxy-and desmethyl-dabrafenib were longer than for parent and hydroxy-dabrafenib (18-20 vs. 5-6 hours). Based on area under the plasma concentration-time curve, dabrafenib, hydroxy-, carboxy-, and desmethyl-dabrafenib accounted for 11%, 8%, 54%, and 3% of the plasma radioactivity, respectively. These results demonstrate that the major route of elimination of dabrafenib is via oxidative metabolism (48% of the dose) and biliary excretion. Based on our understanding of the decarboxylation of carboxy-dabrafenib, a low pH-driven, nonenzymatic mechanism involving participation of the aryl nitrogen is proposed to allow prediction of metabolic oxidation and decarboxylation of drugs containing an aryl nitrogen positioned a to an alkyl (ethyl or t-butyl) side chain.

show abstract

“…However, it has been reported that a carboxylic acid was an intermediate in the C-demethylation of N-tert-butylnorchlorcyclizine and 4-␣-methyl-5␣-cholest-7-en-3␤-ol (Miller and Gaylor, 1970;Kamm and Szuna, 1973), and this carboxylic acid is decarboxylated by a microsomal, cyanide-sensitive enzyme (Gaylor and Mason, 1968). Recently, C-demethylation of the tert-butyl group of a novel dipeptidyl peptidase-4 inhibitor, LC15-0133, has been reported in rat liver microsomes (Yoo et al, 2008). It was further revealed that the C-demethylated metabolite of LC15-0133 was formed by nonenzymatic decarboxylation of the carboxyl metabolite.…”

Section: In Vitro Metabolism Of a Pyridinyl Sulfonamide Analogmentioning

confidence: 97%

CYP2C8- and CYP3A-MediatedC-Demethylation of (3-{[(4-tert-Butylbenzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic Acid (CP-533,536), an EP2 Receptor-Selective Prostaglandin E2 Agonist: Characterization of Metabolites by High-Resolution Liquid Chromatography-Tandem Mass Spectrometry and Liquid Chromatography/Mass Spectrometry-Nuclear Magnetic Resonance

Prakash¹,

Wang²,

O’Connell³

et al. 2008

Drug Metab Dispos

View full text Add to dashboard Cite

CP-533,536, (3-{[(4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic acid (1), an EP2 receptor-selective prostaglandin E2 agonist, is being developed to aid in the healing of bone fractures. To support the development of this program, in vitro metabolism of 1 was investigated in human liver microsomes and major recombinant human cytochrome P450 (P450) isoforms. 1 was metabolized in vitro by at least three recombinant human P450s: CYP3A4, CYP3A5, and CYP2C8. The turnover of 1 was NADPH-dependent and was completely inhibited by ketoconazole and quercetin in the CYP3A4/5 and CYP2C8 incubations, respectively. The major metabolic pathways were caused by oxidation of the tert-butyl moiety to form the -hydroxy metabolite (M4), oxidation of the pyridine moiety, and/or N-dealkylation of the methylphenoxy acetic acid moiety. The alcohol metabolite M4 was further oxidized to the corresponding carboxylic acid M3. In addition to these pathways, three unusual metabolites (M22, M23, and M26) resulting from C-demethylation of the tert-butyl group were identified using high-resolution liquid chromatography/tandem mass spectrometry and liquid chromatography/mass spectrometry/ NMR. The C-demethylated metabolites were not detected on incubation of carboxylic acid metabolite M3 with either human liver microsomes or CYP3A/2C8 isoforms, suggesting that these metabolites were not derived from decarboxylation of M3. A possible mechanism for C-demethylation may involve the oxidation of M4 to form an aldehyde metabolite (M24), followed by P450-mediated deformylation, to give an unstable carbon-centered radical and formic acid. The carbon-centered radical intermediate then undergoes either oxygen rebound to form an alcohol metabolite M23 or hydrogen abstraction leading to an olefin metabolite M26.It has been well documented that EP2-selective prostaglandin E2 (PGE2) agonists, when delivered locally to the periosteal surface or the marrow cavity of bones, increase cortical and cancellous bone formation without the systemic side effects observed with PGE2 (Breyer et al., 2001). Compound 1 (Fig. 1) is a nonprostanoid agonist of the prostaglandin EP2 receptor subtype of PGE2 with significant local bone anabolic activity. It binds to the EP2 receptor with high affinity and selectivity and initiates cAMP signaling via an EP2 receptor-mediated signaling pathway. In in vivo studies, 1 enhanced bone fracture healing in rat and dog fracture models. Furthermore, 1 induced new bone formation and healed critical-sized segmental defects of long bones in the dog (Paralkar et al., 2003). Therefore, it offers a promising therapeutic alternative for the enhancement of bone healing and treatment of bone defects and fractures in humans.Elucidation of biotransformation pathways of a drug candidate in animals and humans, and evaluation of pharmacological and toxicological consequences of its metabolites are very critical to pharmaceutical development and compound progression (Kostiainen et al.,

show abstract

EnzymaticC-Demethylation of 1-[2-(5-tert-Butyl-[1,3,4] oxadiazole-2-carbonyl)-4-fluoro-pyrrolidin-1-yl]-2-(2-hydroxy-1,1-dimethyl-ethylamino)-ethanone (LC15-0133) in Rat Liver Microsomes

Cited by 13 publications

References 10 publications

Metabolism of (2S)-Pterosin A: Identification of the Phase I and Phase II Metabolites in Rat Urine

Metabolism of (2S)-Pterosin A: Identification of the Phase I and Phase II Metabolites in Rat Urine

Metabolism and Disposition of Oral Dabrafenib in Cancer Patients: Proposed Participation of Aryl Nitrogen in Carbon-Carbon Bond Cleavage via Decarboxylation following Enzymatic Oxidation

Contact Info

Product

Resources

About