Cytochrome P450-mediated metabolic interactions between donepezil and tadalafil in human liver microsomes.

Donepezil and tadalafil, commonly prescribed among older persons to treat dementia and erectile dysfunction, respectively, are primarily metabolized by cytochrome P450 (CYP) 3A4. However, the drug-drug interactions (DDIs) of these drugs are unknown. Therefore, this study evaluated the CYP-mediated metabolic interaction between donepezil and tadalafil using pooled human liver microsomes (HLMs) to predict their DDI potential.

Role of cytochrome P450 enzymes in fimasartan metabolism in vitro.

Fimasartan (FMS), an angiotensin II receptor antagonist, is metabolized to FMS S-oxide, FMS N-glucuronide, oxidative desulfurized FMS (BR-A-557), and hydroxy-n-butyl FMSs. The purpose of this study was to characterize enzymes involved in NADPH-dependent FMS metabolism using recombinant enzymes such as cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO), as well as selective chemical inhibitors. The results showed that CYP, but not FMO, plays a major role in FMS metabolism.

Pharmacological Profiles of a Highly Potent and Long-Acting Angiotensin II Receptor Antagonist, Fimasartan, in Rats and Dogs after Oral Administration.

The pharmacological profile of fimasartan, [2-n-butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3-{[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-pyrimidin-4(3H)-one, a new non-peptide angiotensin type 1 (AT)-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, fimasartan showed slow dissociation and irreversible binding to AT subtype receptors in membrane fractions of HEK-293 cells with a K of 0.03 nM and a T of 63.

Characterizing the time-course of antihypertensive activity and optimal dose range of fimasartan via mechanism-based population modeling.

Fimasartan is a novel angiotensin II receptor blocker. Our aims were to characterize the time-course of the antihypertensive activity of fimasartan via a new population pharmacokinetic/pharmacodynamic model and to define its optimal dose range. We simultaneously modelled all fimasartan plasma concentrations and 24-h ambulatory blood pressure monitoring (ABPM) data from 39 patients with essential hypertension and 56 healthy volunteers.

Placental transfer and mammary excretion of a novel angiotensin receptor blocker fimasartan in rats.

Background: Fimasartan (FMS) is a potent angiotensin receptor blocker for the treatment of mild to moderate hypertension. This study aimed to evaluate the transfer of FMS to fetus and breast milk in rats.

Methods: In order to study the transfer to the fetus and nursing pup, pregnant and nursing maternal rats were administered with FMS by a constant intravenous infusion to reach target plasma concentrations of 200 ng/mL and 100 ng/mL.

Absolute bioavailability and pharmacokinetics of the angiotensin II receptor antagonist fimasartan in healthy subjects.

The present study was conducted to determine the absolute bioavailability of fimasartan (FMS; Kanarb(®) ) after the single oral administration of a 60-mg tablet or a single 30-mg intravenous (IV) infusion. This investigation was a randomized, single-dose, open-labeled, two-way crossover study of 16 healthy Korean male subjects. The subjects were divided into two groups (n = 8) and each received either the oral or IV formulation followed by one-week washout period.

Characterization of fimasartan metabolites in human liver microsomes and human plasma.

1. The metabolites of fimasartan (FMS), a new angiotensin II receptor antagonist, were characterized in human liver microsomes (HLM) and human subjects. 2.

Population Pharmacokinetic Modeling of the Enterohepatic Recirculation of Fimasartan in Rats, Dogs, and Humans.

Enterohepatic recirculation (EHC) can greatly enhance plasma drug exposures and therapeutic effects. This study aimed to develop a population pharmacokinetic model that can simultaneously characterize the extent and time-course of EHC in three species using fimasartan, a novel angiotensin II receptor blocker, as a model drug. All fimasartan plasma concentration profiles in 32 rats (intravenous doses, 0.

Glucuronidation of fimasartan, a new angiotensin receptor antagonist, is mainly mediated by UGT1A3.

1. Fimasartan is an angiotensin receptor II antagonist used to treat patients with hypertension. This drug is mainly excreted into bile as either the parent compound or a glucuronide conjugate.

Pharmacokinetics and metabolite profiling of fimasartan, a novel antihypertensive agent, in rats.

1. The objectives of this study were to evaluate the pharmacokinetics and metabolism of fimasartan in rats. 2.

Development of 3D-QSAR CoMSIA models for 5-(biphenyl-2-yl)-1H-tetrazole derivatives as angiotensin II receptor type 1 (AT1) antagonists.

As a development strategy for backups of Fimasartan (1), a comparative molecular similarity indices analysis (CoMSIA) of a set of sixty-five 5-(biphenyl-2-yl)-1H-tetrazole derivatives has been performed to find out the pharmacophore elements for angiotensin II receptor type 1 (AT1) blockade. The most potent compound containing pyrimidin-4(3H)-one ring, Fimasartan (1) was used to align the molecules. As a result, we obtained 3D-QSAR model which provided good predictivity for both the training set (q(2)=0.

Pharmacological characterization of BR-A-657, a highly potent nonpeptide angiotensin II receptor antagonist.

The pharmacological profile of BR-A-657, 2-n-butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3-{[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-pyrimidin-4(3H)-one, a new nonpeptide AT1-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, BR-A-657 displaced [(125)I][Sar(1)-Ile(8)]angiotensin II (Ang II) from its specific binding sites to AT1 subtype receptors in membrane fractions of HEK-293 cells with an IC50 of 0.16 nM.

Synthesis and evaluation of nicotinamide derivative as anti-angiogenic agents.

Previously, we have found that BRN-103, a nicotinamide derivative, inhibits vascular endothelial growth factor (VEGF)-mediated angiogenesis signaling in human endothelial cells. During our continuous efforts to identify more potent anti-angiogenic agents, we synthesized various nicotinamide derivatives and evaluated their anti-angiogenic effects. We found that 2-{1-[1-(6-chloro-5-fluoropyrimidin-4-yl)ethyl]piperidin-4-ylamino}-N-(3-chlorophenyl) pyridine-3-carboxamide (BRN-250) significantly inhibited human umbilical vascular endothelial cells (HUVECs) proliferation, migration, tube formation, and microvessel growth in a concentration range of 10-100 nM.

Fimasartan, anti-hypertension drug, suppressed inducible nitric oxide synthase expressions via nuclear factor-kappa B and activator protein-1 inactivation.

Since inhibition of angiotensin II type 1 (AT1) receptor reduces chronic inflammation associated with hypertension, we evaluated the anti-inflammatory potential and the underlying mechanism of fimasartan, a Korean Food and Drug Administration approved anti-hypertension drug, in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Fimasartan suppressed the expressions of inducible nitric oxide synthase (iNOS) by down-regulating its transcription, and subsequently inhibited the productions of nitric oxide (NO).

Fimasartan, a novel angiotensin II receptor antagonist.

Fimasartan (Kanarb®), an angiotensin II receptor antagonist with selectivity for the AT1 receptor subtype, is a pyrimidinone-related heterocyclic compound that was developed by Boryung Pharm. Co., Ltd.

Synthesis and antihypertensive activity of pyrimidin-4(3H)-one derivatives as losartan analogue for new angiotensin II receptor type 1 (AT1) antagonists.

The discovery, in vitro and in vivo studies of the highly potent AT(1) antagonist 12a (BR-A-657, Fimasartan) antagonists are presented. A series of pyrimidin-4(3H)-one derivatives as losartan analogue were synthesized and evaluated for a novel class of AT(1) receptor antagonists. Among them, 12a containing thioamido moiety displayed both high in vitro functional antagonism and binding affinity [IC(50)=0.

BRN-103, a novel nicotinamide derivative, inhibits VEGF-induced angiogenesis and proliferation in human umbilical vein endothelial cells.

Anti-angiogenesis is regarded as an effective strategy for cancer treatment, and vascular endothelial growth factor (VEGF) plays a key role in the regulations of angiogenesis and vasculogenesis. In the present study, the authors synthesized five novel nicotinamide derivatives which structurally mimic the receptor tyrosine kinase inhibitor sunitinib and evaluated their anti-angiogenic effects. Transwell migration assays revealed that 2-(1-benzylpiperidin-4-yl) amino-N-(3-chlorophenyl) nicotinamide (BRN-103), among the five derivatives most potently inhibited VEGF-induced human umbilical vein endothelial cells (HUVECs).

Safety, tolerability, pharmacokinetics, and pharmacodynamics of fimasartan following single and repeated oral administration in the fasted and fed states in healthy subjects.

Background And Objectives: Fimasartan (BR-A-657) is a novel, non-peptide angiotensin II receptor antagonist with a selective type I receptor blockade effect. Two first-in-human studies investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of fimasartan.

Methods: Fasted single oral tablet doses of fimasartan 20-480 mg or placebo were administered to 40 healthy male subjects (aged 19-54 years) in a double-blind, randomized, sequential-group design.

Simultaneous determination of fimasartan, a novel antihypertensive agent, and its active metabolite in rat plasma by liquid chromatography-tandem mass spectrometry.

Fimasartan, 2-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H tetrazol -5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one (BR-A-657), is a novel angiotensin II receptor blocker exhibiting potent and selective AT1 receptor blocking activity. This study reports the liquid chromatography-tandem mass spectrometry assay for the simultaneous determination of fimasartan and its active metabolite, BR-A-557, in rat plasma. The assay was validated to demonstrate the specificity, linearity, recovery, lower limit of quantification, accuracy, precision and stability.