Metabolic profiling of a novel antithrombotic compound, S002‐333 and enantiomers: metabolic stability, species comparison and <i>in vitro–in vivo</i> extrapolation

Saxena, Ashish; Valicherla, Guru R.; Jain, Girish Kumar; Bhatta, Rabi Sankar; Saxena, Anil Kumar; Gayen, Jiaur R.

doi:10.1002/bdd.1995

Cited by 5 publications

(4 citation statements)

References 28 publications

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“…In another study, Saxena et al (102) characterized the metabolism of S002-333 [2-(4'-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid amide] and its enantiomers, S004-1032 and S007-1558, using liver microsomes from different species. In case of compound S002-333, the highest CL int values were noted in MnLM and were comparable to the values for RLM.…”

Section: In Vitro-in Vivo Extrapolationmentioning

confidence: 99%

Metabolic stability and its role in the discovery of new chemical entities

et al. 2019

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Determination of metabolic profiles of new chemical entities is a key step in the process of drug discovery, since it influences pharmacokinetic characteristics of therapeutic compounds. One of the main challenges of medicinal chemistry is not only to design compounds demonstrating beneficial activity, but also molecules exhibiting favourable pharmacokinetic parameters. Chemical compounds can be divided into those which are metabolized relatively fast and those which undergo slow biotransformation. Rapid biotransformation reduces exposure to the maternal compound and may lead to the generation of active, non-active or toxic metabolites. In contrast, high metabolic stability may promote interactions between drugs and lead to parent compound toxicity. In the present paper, issues of compound metabolic stability will be discussed, with special emphasis on its significance, in vitro metabolic stability testing, dilemmas regarding in vitro-in vivo extrapolation of the results and some aspects relating to different preclinical species used in in vitro metabolic stability assessment of compounds.

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Section: In Vitro-in Vivo Extrapolationmentioning

confidence: 99%

Metabolic stability and its role in the discovery of new chemical entities

et al. 2019

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“…In‐vitro CL int of S009–0629 at 5 and 10 µM was calculated as 5.10 ± 0.46 and 4.94 ± 0.47 µL/min/mg, respectively. Scaled in‐vitro CL int in rat liver microsomes was calculated using the values of liver weight of 10 g, rat body weight of 250 g and MPPGL of 45 mg/kg (Saxena et al, ). Scaled in‐vitro CL int of S009–0629 at 5 and 10 µM was calculated as 9.18 ± 0.82 and 8.90 ± 0.84 mL/min/kg of bw.…”

Section: Resultsmentioning

confidence: 99%

“…The in‐vitro half‐life ( t 1/2 ) was calculated as 0.693/K. The in‐vitro intrinsic clearance (in‐vitro CL int ) was calculated using the Equation (Marques et al, ; Saxena et al, ).

{normalI normaln normalv normali normalt normalr normalo normalC normalL}_{normali normaln normalt} = \frac{0.693}{t_{1 / 2}} \times \frac{normalV normalo normall normalu normalm normale normalo normalf normalr normale normala normalc normalt normali normalo normaln normalm normali normalx normalt normalu normalr normale true(normalm normalL true)}{normalm normalg normalo normalf normalp normalr normalo normalt normale normali normaln normalr normale normala normalc normalt normali normalo normaln}

…”

Section: Methodsmentioning

confidence: 99%

Evaluation of oral pharmacokinetics, in vitro metabolism, blood partitioning and plasma protein binding of novel antidiabetic agent, S009‐0629 in rats

Valicherla

Italiya

Gupta

et al. 2018

Drug Development Research

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S009-0629 [methyl-8-(methylthio)-2-phenyl-6-p-tolyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate] is a novel antidiabetic agent with PTP1B inhibitory activity. In this study, we have investigated the in vitro metabolic stability, plasma protein binding, blood partitioning, and oral pharmacokinetic study of S009-0629 in rats. The plasma protein binding, blood partitioning, and metabolic stability were determined by HPLC method. The oral pharmacokinetic study was analyzed by liquid chromatography coupled mass spectrometry (LC-MS/MS) method. The plasma protein binding of S009-0629 using modified charcoal adsorption method at 5 and 10 µg/mL was 80.58 ± 1.04% and 81.95 ± 1.15%, respectively. The K of S009-0629 was independent of concentration and time. The in-vitro half-life of S009-0629 at 5 and 10 µM using rat liver microsomes was determined as 273 ± 24.46 and 281.67 ± 26.53 min, respectively. After oral administration, S009-0629 exhibited C 55.51 ± 1.18 ng/mL was observed at 18 hr (t ). S009-0629 was found to have the large apparent volume of distribution (1,894.93 ± 363.67 L/kg). Oral in-vivo t of S009-0629 was found to be 41.23 ± 5.96 hr. A rapid and highly sensitive LC-MS/MS method was validated for S009-0629 in rat plasma. S009-0629 has high plasma protein binding and low hepatic extraction. S009-0629 has no affinity with human P-gp and BCRP in ATPase assay. After oral dosing, S009-0629 has slow absorption and elimination in rats.

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“…With these approaches still under investigation, we took an initiative to develop a clinically useful synthetic molecule targeting platelet–collagen interaction at the sites of arterial injury or plaques. This compound 6b (CDRI-S002-333) is undergoing pharmacokinetic − and toxicological studies. From the pharmacokinetic studies it was observed that the isomer 6c or 6d does not interconvert in vivo.…”

Section: Discussionmentioning

confidence: 99%

Novel Glycoprotein VI Antagonists as Antithrombotics: Synthesis, Biological Evaluation, and Molecular Modeling Studies on 2,3-Disubstituted Tetrahydropyrido(3,4-b)indoles

Bhunia

Misra²,

Khan³

et al. 2016

J. Med. Chem.

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The development of small molecule inhibitors targeting GPVI has promising therapeutic role, as they inhibit arterial thrombosis with limited risk of bleeding. Among the compounds showing in vivo antithrombotic activity, the most active compound 6b (ED = 28.36 μmol/kg po in mice) showed improved inhibition for collagen (IC = 6.7 μM), CRP-XL (IC = 53.5 μM), and convulxin (CVX) (IC = 5.7 μM) mediated platelet aggregation as compared to losartan (LOS) (collagen, IC = 10.4 μM; CRP-XL, IC = 158 μM; CVX, IC = 11 μM) than any of its enantiomers S (6c) (collagen, IC = 25.3 μM; CRP-XL, IC = 181.4 μM; CVX, IC = 9 μM) and R (6d) (collagen, IC = 126.3 μM; CRP-XL, IC > 500 μM; CVX, IC = 86.8 μM). Compound 6b also inhibited platelet P-selectin expression and thus may diminish atherosclerosis. The molecular interactions of both enantiomers 6c and 6d at the GPVI receptor have been explained through docking studies.

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Metabolic profiling of a novel antithrombotic compound, S002‐333 and enantiomers: metabolic stability, species comparison and in vitro–in vivo extrapolation

Cited by 5 publications

References 28 publications

Metabolic stability and its role in the discovery of new chemical entities

Metabolic stability and its role in the discovery of new chemical entities

Evaluation of oral pharmacokinetics, in vitro metabolism, blood partitioning and plasma protein binding of novel antidiabetic agent, S009‐0629 in rats

Novel Glycoprotein VI Antagonists as Antithrombotics: Synthesis, Biological Evaluation, and Molecular Modeling Studies on 2,3-Disubstituted Tetrahydropyrido(3,4-b)indoles

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