A Validated Chiral LC-MS/MS Method for the Enantioselective Determination of (S)-(+)- and (R)-(-)-Ibuprofen in Dog Plasma: Its Application to a Pharmacokinetic Study.

The purpose of this study was to develop a method for simultaneously separating ibuprofen enantiomers using electrospray ionization (ESI) liquid chromatography with tandem mass spectrometry (LC-MS/MS). LC-MS/MS was operated with negative ionization and multiple reaction monitoring modes; transitions were monitored at m/z of 205.1 > 160.9 for ibuprofen enantiomers, 208.1 > 163.9 for (S)-(+)-ibuprofen-d3 [internal standard 1 (IS1)], and 253.1 > 208.9 for (S)-(+)-ketoprofen (IS2), respectively. In a one-step liquid-liquid extraction, 10 µL plasma was extracted with ethyl acetate:methyl tertiary-butyl ether of 7:3. Enantiomer chromatographic separation was carried out with an isocratic mobile phase consisting of 0.008% formic acid in water-methanol (v/v) at a flow rate of 0.4 mL/min on a CHIRALCEL® OJ-3R column (150 × 4.6 mm, 3 µm). This method was fully validated for each enantiomer and results were in compliance with the regulatory guidelines of the U.S. Food and Drug Administration and the Korea Ministry of Food and Drug Safety. The validated assay was executed for nonclinical pharmacokinetic studies after oral and intravenous administration of racemic ibuprofen and dexibuprofen in beagle dogs.

Development of a Rapid LC-MS/MS Method for Simultaneous Quantification of Donepezil and Tadalafil in Rat Plasma: Its Application in a Pharmacokinetic Interaction Study after Oral Administration in Rats.

This study aimed to establish a simple and sensitive analytical method to simultaneously quantify donepezil (DPZ) and tadalafil (TAD) in rat plasma using lansoprazole (LPZ) as an internal standard (IS) by using liquid chromatography tandem mass spectrometry. The fragmentation pattern of DPZ, TAD, and IS was elucidated using multiple reaction monitoring in electrospray ionization positive ion mode for the quantification of precursor to production at m/z 380.1 → 91.2 for DPZ, m/z 390.2 → 268.1 for TAD, and m/z 370.3 → 252.0 for LPZ. The extracted DPZ and TAD from plasma using acetonitrile-induced protein precipitation was separated using Kinetex C18 (100 × 2.1 mm, 2.6 µm) column with a gradient mobile phase system consisting of 2 mM ammonium acetate and 0.1% formic acid in acetonitrile at a flow rate of 0.25 mL/min for 4 min. The selectivity, lower limit of quantification, linearity, precision, accuracy, stability, recovery, and matrix effect of this developed method was validated according to the guidelines of the U.S. Food and Drug Administration and the Ministry of Food and Drug Safety of Korea. The established method achieved acceptance criteria in all validation parameters, ensuring reliability, reproducibility, and accuracy, and was successfully implemented in a pharmacokinetic study on the co-administration of DPZ and TAD orally in rats.

Regional Absorption of Fimasartan in the Gastrointestinal Tract by an Improved in situ Absorption Method in Rats.

The aim of the present study was to assess the regional absorption of fimasartan by an improved in situ absorption method in comparison with the conventional in situ single-pass perfusion method in rats. After each gastrointestinal segment of interest was identified, fimasartan was injected into the starting point of each segment and the unabsorbed fimasartan was discharged from the end point of the segment. Blood samples were collected from the jugular vein to evaluate the systemic absorption of the drug. The relative fraction absorbed (Fabs,relative) values in the specific gastrointestinal region calculated based on the area under the curve (AUC) values obtained after the injection of fimasartan into the gastrointestinal segment were 8.2% ± 3.2%, 23.0% ± 12.1%, 49.7% ± 11.5%, and 19.1% ± 11.9% for the stomach, duodenum, small intestine, and large intestine, respectively, which were comparable with those determined by the conventional in situ single-pass perfusion. By applying the fraction of the dose available at each gastrointestinal segment following the oral administration, the actual fraction absorbed (F'abs) values at each gastrointestinal segment were estimated at 10.9% for the stomach, 27.1% for the duodenum, 40.7% for the small intestine, and 5.4% for the large intestine, which added up to the gastrointestinal bioavailability (FX·FG) of 84.1%. The present method holds great promise to assess the regional absorption of a drug and aid to design new drug formulations.

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. CYP2C9, CYP3A4, and CYP3A5 were involved in the formation of FMS S-oxide, which was further metabolized to BR-A-557 by CYP3A4/5. CYP2C9 played an exclusive role in n-butyl hydroxylation. The specificity constant (kcat/Km) values for S-oxidation by CYP2C9, CYP3A4, and CYP3A5 were 0.21, 0.34, and 0.19 µM-1∙min-1, respectively. The kcat/Km values of hydroxylation at the 1-, 2-/3-, and 4-n-butyl group in CYP2C9 were 0.0076, 0.041, and 0.035 µM-1∙min-1, respectively. The kcat and Km values provide information for the prediction of FMS metabolism in vivo. In addition, simultaneous determination of the FMS metabolites may be used to evaluate CYP2C9 and CYP3A4/5 activity.

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 (AT1)-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 AT1 subtype receptors in membrane fractions of HEK-293 cells with a Kd of 0.03 nM and a T1/2 of 63.7 min. The inhibitory effect of fimasartan on angiotensin II (Ang II)-induced contraction persisted longer after washout than that of losartan or candesartan. In conscious rats, a single dose of fimasartan (0.3, 1, or 3 mg/kg; per os (p.o.)) dose-dependently antagonized Ang II-induced pressor responses. Both orally administrated fimasartan and losartan dose-dependently decreased mean arterial pressure in furosemide-treated rats and dogs, and fimasartan administered orally at 1, 3, or 10 mg/kg reduced blood pressure in conscious spontaneously hypertensive rats. Taken together, these findings indicate that fimasartan has potent and sustained binding affinity at the AT1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in various conscious rats and dogs models after its oral administration.

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. Patients received placebo, 20, 60, or 180mg fimasartan every 24h for 28days and healthy volunteers received placebo or 20 to 480mg as a single oral dose or as seven doses every 24h. External validation was performed using data on 560 patients from four phase II or III studies. One turnover model each was used to describe diastolic and systolic blood pressure. The input rates into these compartments followed a circadian rhythm and were inhibited by fimasartan. The average predicted (observed) diastolic blood pressure over 24-h in patients decreased by 10.1±7.5 (12.6±9.2; mean±SD)mmHg for 20mg, 14.2±7.0 (15.1±9.3) mmHg for 60mg, and 15.9±6.8 (11.5±9.9)mmHg for 180mg daily relative to placebo. The model explained the saturation of antihypertensive activity by counter-regulation at high fimasartan concentrations. Drug effect was maximal at approximately 23ng/mL fimasartan for diastolic and 12ng/mL for systolic blood pressure. The proposed mechanism-based population model characterized the circadian rhythm of ABPM data and the antihypertensive effect of fimasartan. After internal and external model validation, 30 to 60mg oral fimasartan given once daily was predicted as optimal dose range.

Effects of Hot Water Extracts from Polygonum multiflorum on Ovariectomy Induced Osteopenia in Mice.

Polygonum multiflorum (PM), a traditional Chinese medicine, is used to treat various diseases including nonalcoholic fatty liver disease and hyperlipidemia. However, the influence of PM on osteoporosis in animals is unclear. The present study investigated the antiosteoporotic effect of PM on bone mass in ovariectomized (OVX) mice and its possible mechanism of action. Twenty-five female C3H/HeN mice were divided into five groups of five mice as follows. Sham-operated control mice received daily oral gavage of an equal volume of water, and OVX mice received daily oral gavage of water or an injection of ß-estradiol or PM for 6 weeks. Administration of PM significantly suppressed body weight and organs weight and increased weight and length of bone compared with the OVX group. Treatment with PM reversed osteopenia in OVX mice, thereby improving the bone morphometric parameters. Moreover, histological analysis using hematoxylin and eosin staining showed that PM inhibited OVX-induced bone loss. Serum estradiol and bone alkaline phosphatase levels were significantly decreased in the OVX group, with the levels increasing with PM treatment. In addition, tartrate-resistant acid phosphatase activity was inhibited by PM in OVX mice. These results suggest that PM is effective in preventing bone loss in OVX mice.

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. The concentrations of FMS in plasma, placenta, amniotic fluid, fetus, and milk were determined by a validated LC-MS/MS assay. RESULTS: Upon constant intravenous infusion, the plasma FMS concentration reached the target steady state concentrations (Css = 200 ng/mL and 100 ng/mL) in 24 h. The tissue-to-plasma partition coefficients (Kp) for placenta, amniotic fluid, and milk were obtained based on the observed FMS concentrations in the tissues and Css. The Kp values for all tissues were not different between high (Css = 200 ng/mL) and low (Css = 100 ng/mL) dose groups. While the mean Kp of the placenta was 44.6-59.0 %, the mean Kp was 1.3-1.7 % for the amniotic fluid and 14.9-17.0 % for fetus. The mean Kp of milk was 10.4-15.2 %. CONCLUSIONS: Placental transfer and milk excretion of FMS was relatively lower compared to other angiotensin receptor blockers.

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. The Cmax (ng/ml) and AUC∞ (h · ng/ml) following oral and IV administration were 62.4 ± 48.6 and 291.1 ± 121.7; and 683.3 ± 104.3 and 782.3 ± 112.7 (mean ± SD), respectively. The Tmax (h) were 3.0 h (range: 0.5-5.0 h) and 1.0 h (range: 0.8-1.0 h) in the test and reference groups, respectively. The terminal elimination half-lives (t1/2 , h) were similar (5.8 and 5.5 h, respectively) indicating that the route of administration did not influence the absorption or elimination of FMS. The systemic clearance (CL, L/h) and the volume of distribution at steady-state (Vdss , L) were 331.3 ± 444.5 L/h and 403.3 ± 710.4 L following oral administration and 39.1 ± 5.3 L/h and 42.4 ± 25.5 L following IV administration. The absolute bioavailability of the FMS tablet was 18.6%.

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. We developed a method for a simultaneous quantitative and qualitative analysis using predictive multiple reaction monitoring information-dependent acquisition-enhanced product ion scanning. To characterize metabolic reactions, FMS metabolites were analyzed using quadrupole-time of flight mass spectrometer in full-scan mode. 3. The structures of metabolites were confirmed by comparison of chromatographic retention times and mass spectra with those of authentic metabolite standards. 4. In the cofactor-dependent microsomal metabolism study, the half-lives of FMS were 56.7, 247.9 and 53.3 min in the presence of NADPH, UDPGA and NADPH + UDPGA, respectively. 5. The main metabolic routes in HLM were S-oxidation, oxidative desulfuration, n-butyl hydroxylation and N-glucuronidation. 6. In humans orally administered with 120 mg FMS daily for 7 days, the prominent metabolites were FMS S-oxide and FMS N-glucuronide in the 0-8-h pooled plasma sample of each subject. 7. This study characterizes, for the first time, the metabolites of FMS in humans to provide information for its safe use in clinical medicine.

Simultaneous determination of phenoxyethanol and its major metabolite, phenoxyacetic acid, in rat biological matrices by LC-MS/MS with polarity switching: Application to ADME studies.

This study describes the development of a simple LC-ESI-MS/MS method with polarity switching for the simultaneous analysis of phenoxyethanol (PE) and its major metabolite, phenoxyacetic acid (PAA), in rat plasma, urine, and 7 different tissues. The assay was validated to demonstrate the linearity, precision, accuracy, LLOQ, recovery, and stability by using the matrix matched QC samples. The assay achieved the LLOQ of 10 and 20 ng/mL of PE and PAA, respectively, for plasma samples and the LLOQ of 20 and 50 ng/mL of PE and PAA, respectively, for urine and tissue samples. This method was successfully applied to the percutaneous absorption, distribution, metabolism, and excretion studies in rats. The absolute topical bioavailability of PE was 75.4% and 76.0% for emulsion and lotion, respectively. Conversion of PE to PAA was extensive, with the average AUCPAA-to-AUCPE ratio being 4.4 and 5.3 for emulsion and lotion, respectively. The steady-state tissue-to-plasma PE concentration ratio (Kp) was higher than unity for kidney, spleen, heart, brain, and testis and was lower (≤0.6) for lung and liver, while the metabolite Kp ratio was higher than unity for kidney, liver, lung, and testis and was lower (≤0.3) for other tissues. Findings of this study may be useful to evaluate the relationship between exposure and toxic potential of PE in risk assessment.

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, 0.3-3 mg/kg; oral doses, 1-10 mg/kg), 34 dogs (intravenous doses, 0.3-1 mg/kg; oral doses, 1-10 mg/kg), and 42 healthy volunteers (single or multiple oral doses, 20-480 mg) were determined via liquid chromatography-tandem mass spectrometry (LC-MS/MS) and simultaneously modeled in S-ADAPT. The proposed model quantitatively characterized EHC in three species after oral and intravenous dosing. The median (range) fraction of drug undergoing recirculation was 76.3% (64.9-88.7%) in rats, 33.3% (24.0-45.9%) in dogs, and 65.6% (56.5-72.0%) in humans. In the presence compared with the absence of EHC, the area under the curve in plasma was predicted to be 4.22-fold (2.85-8.85) as high in rats, 1.50-fold (1.32-1.85) in dogs, and 2.91-fold (2.30-3.57) in humans. The modeled oral bioavailability in rats (median (range), 38.7% (20.0-59.8%)) and dogs (median, 7.13% to 15.4%, depending on the formulation) matched the non-compartmental estimates well. In humans, the predicted oral bioavailability was 25.1% (15.1-43.9%) under fasting and 18.2% (12.2-31.0%) under fed conditions. The allometrically scaled area under the curve predicted from rats was 420 ng·h/mL for 60 mg fimasartan compared with 424 ± 63 ng·h/mL observed in humans. The developed population pharmacokinetic model can be utilized to characterize the impact of EHC on plasma drug exposure in animals and humans.

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. In this study, we examined the glucuronidation of fimasartan and characterized the UDP-glucuronosyltransferases (UGTs) responsible for the glucuronidation. 2. Only one type of fimasartan glucuronide was observed after incubation with pooled human liver microsomes (HLMs) and was identified as an N2-glucuronide based on comparison with an authentic standard. 3. Among the 12 UGT isoforms tested, UGT1A1, UGT1A3 and UGT2B7 showed catalytic activity toward fimasartan glucuronidation. The intrinsic clearance (CLint) of UGT1A3 was 68.5- and 21.4-fold higher than that of UGT1A1 and UGT2B7, respectively, and the estimated relative contribution of UGT1A3 in human liver was 94.1%. Both chemical inhibition and correlation studies demonstrated that fimasartan glucuronidation activity in HLMs was significantly related with UGT1A3 activity. Fimasartan glucuronide was identified as a substrate for P-glycoprotein (Pgp) and breast cancer response protein (BCRP). 4. These findings collectively indicate that UGT1A3 is the major UGT isoform responsible for the glucuronidation of fimasartan, and this glucuronide is excreted from hepatocytes via MDR1 and BCRP.

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. Unlabeled fimasartan or radiolabeled [(14)C]fimasartan was dosed by intravenous injection or oral administration to rats. Concentrations of unlabeled fimasartan in the biological samples were determined by a validated LC/MS/MS assay. Total radioactivity was quantified by liquid scintillation counting and the radioactivity associated with the metabolites was analyzed by using the radiochemical detector. Metabolite identification was conducted by product ion scanning using LC/MS/MS. 3. After oral administration of [(14)C]fimasartan, total radioactivity was found primarily in feces. In bile duct cannulated rats, 58.8 ± 14.4% of the radioactive dose was excreted via bile after oral dosing. Major metabolites of fimasartan including the active metabolite, desulfo-fimasartan, were identified, yet none represented more than 7.2% of the exposure of the parent drug. Fimasartan was rapidly and extensively absorbed and had an oral bioavailability of 32.7-49.6% in rats. Fimasartan plasma concentrations showed a multi-exponential decline after oral administration. Double peaks and extended terminal half-life were observed, which was likely caused by enterohepatic recirculation. 4. These results provide better understanding on the pharmacokinetics of fimasartan and may aid further development of fimasartan analogs.

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. In a functional assay using isolated rabbit thoracic aorta, BR-A-657 inhibited the contractile response to Ang II (pD'2: 9.15) with a significant reduction in the maximum. In conscious rats, BR-A-657 (0.01, 0.1, 1 mg/kg; intravenously (i.v.)) dose-dependently antagonized Ang II-induced pressor responses. In addition, BR-A-657 dose-dependently decreased mean arterial pressure in furosemide-treated rats and renal hypertensive rats. Moreover, BR-A-657 given orally at 1 and 3 mg/kg reduced blood pressure in conscious renal hypertensive rats. Taken together, these findings indicate that BR-A-657 is a potent and specific antagonist of Ang II at the AT1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in conscious rats.

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)=0.846, r(2)=0.975) and the external test set (rpred(2)=0.980). This model would guide the design of backups for Fimasartan (1), a launched oral antihypertensive agent.

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. Furthermore, BRN-250 inhibited the VEGF-induced phosphorylation and intracellular tyrosine kinase activity of VEGF receptor 2 (VEGFR2) and the activation of its downstream AKT pathway. Taken together, these findings suggest that BRN-250 be considered a potential lead compound for cancer therapy.

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). In addition, fimasartan attenuated LPS-induced transcriptional and DNA-binding activities of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). These reductions were accompanied by parallel reductions in the nuclear translocation of NF-κB and AP-1. Taken together, our data suggest that fimasartan down-regulates the expression of the iNOS in macrophages via NF-κB and AP-1 inactivation.

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. Among numerous synthetic derivatives, fimasartan was chosen as a new drug candidate through in vitro and in vivo screening studies. Pharmadynamic-pharmacokinetic properties and safety profiles were determined in a series of nonclinical and clinical studies. Fimasartan is a new angiotensin receptor blocker, and the first new molecular entity acting on cardiovascular system approved by Korean Food and Drug Administration for the treatment of essential hypertension in September 2010. Further development process for combination therapy and overseas registration is currently ongoing.

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). In addition, BRN-103 dose-dependently inhibited VEGF-induced migration, proliferation, and capillary-like tube formation of HUVECs and vessel sprouting from mouse aortic rings. To understand the molecular mechanisms responsible for these activities, the authors examined the effect of BRN-103 on VEGF signaling pathways in HUVECs. BRN-103 was found to suppress the VEGF-induced phosphorylation of VEGF receptor 2 (VEGR2) and the activations of AKT and eNOS. Taken together, these results suggest that BRN-103 inhibits VEGF-mediated angiogenesis signaling in human endothelial cells.