<i>In Vitro</i>and<i>In Vivo</i>Characterizations of Chiglitazar, a Newly Identified PPAR Pan-Agonist

He, Bing; Ning, Zhiqiang; Li, Z. B.; Song, Shan; Pan, Desi; Ko, Ben C.B.; Li, P. P.; Shen, Zhufang; Dou, Guifang; Zhang, B. L.; Lu, Xianping; Gao, Yue

doi:10.1155/2012/546548

Cited by 43 publications

(37 citation statements)

References 41 publications

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“…It is well known that MET is mainly absorbed in the small intestine and distributed in organ tissues such as gastrointestinal, liver, and renal, whereas it is not metabolized in the liver . CHI was reported to be metabolized through CYP3A4 in the liver . MET is a superior substrate for renal organic cation transporter (OCT) 2 and is also slightly affected by OCT1 in its hepatic uptake .…”

Section: Discussionmentioning

confidence: 99%

“…22,23 CHI was reported to be metabolized through CYP3A4 in the liver. 12 MET is a superior substrate for renal organic cation transporter (OCT) 2 and is also slightly affected by OCT1 in its hepatic uptake. 23 Regarding the influences of CHI on MET, based on in vitro cell culture model, we found that CHI only slightly inhibited the uptake of MET mediated by OCT2 in human cells (data not shown), which was consistent with the result of this clinical study.…”

Section: Discussionmentioning

confidence: 99%

“…Chiglitazar (CHI), a novel configuration‐restricted non‐TZD PPAR pan‐agonist, is currently in its phase 3 clinical development for treatment of patients with T2DM in China (http://www.chinadrugtrials.org.cn/, with registration number CTR20131996; https://clinicaltrials.gov, with registration identifier number NCT02121717). Previous studies, both in vitro and in vivo, demonstrated that CHI had moderate transcription activity in PPAR‐α, PPAR‐γ, and PPAR–δ types . It could upregulate the expression of genes like ANGPTL4 and PDK4 , which are involved in glucose and lipid metabolism.…”

mentioning

confidence: 99%

“…Previous studies, both in vitro and in vivo, demonstrated that CHI had moderate transcription activity in PPAR-α, PPAR-γ , and PPAR-δ types. 11,12 It could upregulate the expression of genes like ANGPTL4 and PDK4, which are involved in glucose and lipid metabolism. And the early phase of the clinical trial of CHI evidenced its effectiveness in ameliorating glycometabolism.…”

mentioning

confidence: 99%

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Study on Drug‐Drug Interactions Between Chiglitazar, a Novel PPAR Pan‐Agonist, and Metformin Hydrochloride in Healthy Subjects

Liu

Zhang

et al. 2019

Clinical Pharm in Drug Dev

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Chiglitazar (CHI) is a potent and selective peroxisome proliferator‐activated receptor potentially for the treatment of patients with type 2 diabetes mellitus (T2DM). An open‐label, randomized, 3‐period crossover and self‐controlled study was conducted to investigate drug‐drug interaction potential between CHI and metformin hydrochloride (MET). Eligible subjects received a single oral dose of CHI (48 mg), MET (1000 mg), or a combination in each period, followed by serial blood sampling collected for up to 48 hours postdose, and safety was assessed throughout the trial. The area under the plasma concentration‐time curves from time 0 to 48 hours (AUC0‐48 h) of CHI was similar following administration alone or with MET (AUC0‐48h, 12 540 ng·h/mL [9811‐15 269 ng·h/mL] vs 12 130 ng·h/mL [9304‐14 956 ng·h/mL]; 90% confidence interval [CI] of its geometric mean ratio [GMR], 89.7%–103.8%), whereas the maximum concentration (Cmax) of CHI was reduced during coadministration, as its 90%CI of the GMR was slightly outside the acceptance range for bioequivalence (Cmax, 1620 ng/mL [1418‐1822 ng/mL] vs 1420 ng/mL [1049‐1791 ng/mL], 90%CI GMR, 77.%‐94.1%). However, it was not considered clinically meaningful. The MET exposures remained consistent in the absence or presence of CHI (AUC0‐48 h, 12 570 ng·h/mL [10681‐14 459 ng·h/mL] vs 13 190 [10973‐15 407 ng·h/mL); 90%CI of GMR: 99.1%‐110.5%; Cmax, 1790 ng/mL [1448–2132 ng/mL] vs 1820 ng/mL [1510‐2130 ng/mL]; 90%CI of GMR, 94.2%–110.9%). No moderate to severe adverse events were reported. Our study indicated no clinically significant pharmacokinetic drug‐drug interaction between CHI and MET and demonstrated good tolerance in subjects. These results support future application of CHI in combination with MET for treatment of T2DM.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Study on Drug‐Drug Interactions Between Chiglitazar, a Novel PPAR Pan‐Agonist, and Metformin Hydrochloride in Healthy Subjects

Liu

Zhang

et al. 2019

Clinical Pharm in Drug Dev

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“…Chiglitazar (Figure 2), discovered and synthesized by Shenzhen Chipscreen Biosciences Ltd., has recently completed phase III clinical trials in China. Chiglitazar is a non-TZD insulin sensitizer and is described as a nonselective pan-agonist to the three PPAR receptor subtypes shown to act on the PPARα, PPARβ/δ, and PPARγ subtypes with an EC 50 value of 1.2, 1.7, and 0.08 μM, respectively [33,66,67]. Research into chiglitazar's activity has significantly progressed over time.…”

Section: Introductionmentioning

confidence: 99%

To Probe Full and Partial Activation of Human Peroxisome Proliferator-Activated Receptors by Pan-Agonist Chiglitazar Using Molecular Dynamics Simulations

et al. 2020

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Chiglitazar is a promising new-generation insulin sensitizer with low reverse effects for the treatment of type II diabetes mellitus (T2DM) and has shown activity as a nonselective pan-agonist to the human peroxisome proliferator-activated receptors (PPARs) (i.e., full activation of PPARγ and a partial activation of PPARα and PPARβ/δ). Yet, it has no high-resolution complex structure with PPARs and its detailed interactions and activation mechanism remain unclear. In this study, we docked chiglitazar into three experimentally resolved crystal structures of hPPAR subtypes, PPARα, PPARβ/δ, and PPARγ, followed by 3 μs molecular dynamics simulations for each system. Our MM-GBSA binding energy calculation revealed that chiglitazar most favorably bound to hPPARγ (-144.6 kcal/mol), followed by hPPARα (-138.0 kcal/mol) and hPPARβ (-135.9 kcal/mol), and the order is consistent with the experimental data. Through the decomposition of the MM-GBSA binding energy by residue and the use of two-dimensional interaction diagrams, key residues involved in the binding of chiglitazar were identified and characterized for each complex system. Additionally, our detailed dynamics analyses support that the conformation and dynamics of helix 12 play a critical role in determining the activities of the different types of ligands (e.g., full agonist vs. partial agonist). Rather than being bent fully in the direction of the agonist versus antagonist conformation, a partial agonist can adopt a more linear conformation and have a lower degree of flexibility. Our finding may aid in further development of this new generation of medication.

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Design of Improved Antidiabetic Drugs: A Journey from Single to Multitarget Agents

2022

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Multifactorial diseases exhibit a complex pathophysiology with several factors contributing to their pathogenesis and development. Examples of such disorders are neurodegenerative (e. g. Alzheimer's, Parkinson's) and cardiovascular diseases (e. g. atherosclerosis, metabolic syndrome, diabetes II). Traditional therapeutic approaches with single‐target drugs have been proven, in many cases, unsatisfactory for the treatment of multifactorial diseases such as diabetes II. The well‐established by now strategy of multitarget drugs is constantly gaining interest and momentum, as a more effective approach. The development of pharmacomolecules able to simultaneously modulate multiple relevant‐to‐the‐disease targets has already several successful examples in various fields and has, as such, inspired the design of multitarget antidiabetic agents; this review highlights the design aspect and efficacy of this approach for improved antidiabetics by presenting several examples of successful pharmacophore combinations in (multitarget) agents that modulate two or more molecular targets involved in diabetes II, resulting in a superior antihyperglycemic profile.

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In VitroandIn VivoCharacterizations of Chiglitazar, a Newly Identified PPAR Pan-Agonist

Cited by 43 publications

References 41 publications

Study on Drug‐Drug Interactions Between Chiglitazar, a Novel PPAR Pan‐Agonist, and Metformin Hydrochloride in Healthy Subjects

Study on Drug‐Drug Interactions Between Chiglitazar, a Novel PPAR Pan‐Agonist, and Metformin Hydrochloride in Healthy Subjects

To Probe Full and Partial Activation of Human Peroxisome Proliferator-Activated Receptors by Pan-Agonist Chiglitazar Using Molecular Dynamics Simulations

Design of Improved Antidiabetic Drugs: A Journey from Single to Multitarget Agents

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