Boryung Pharm. Co.

Ansan, South Korea

Boryung Pharm. Co.

Ansan, South Korea
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Kim T.H.,Sungkyunkwan University | Shin S.,Wonkwang University | Bashir M.,Covance Laboratories Inc. | Chi Y.H.,Boryung Pharm. Co. | And 9 more authors.
Xenobiotica | Year: 2014

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


Choi M.J.,Kyung Hee University | Kwon G.H.,Kyung Hee University | Han N.S.,Boryung Pharm. Co. | Yoo B.W.,Boryung Pharm. Co. | And 5 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

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 (q2 = 0.846, r2 = 0.975) and the external test set (rpred2=0.980). This model would guide the design of backups for Fimasartan (1), a launched oral antihypertensive agent. © 2013 Elsevier Ltd. All rights reserved.


Kim T.W.,Kyung Hee University | Yoo B.W.,Boryung Pharm. Co. | Lee J.K.,Boryung Pharm. Co. | Kim J.H.,Boryung Pharm. Co. | And 3 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

The discovery, in vitro and in vivo studies of the highly potent AT1 antagonist 12a (BR-A-657, Fimasartan) 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 = 0.42 and 0.13 nM, respectively] and inhibited strongly in vivo AngII-induced pressor response in pithed rats with an ED 50 of 0.018 mg/kg. Moreover, in vivo evaluation in furosemide-treated rat and conscious renal hypertensive rat models and the pharmacokinetic study showed that 12a is a highly potent and orally active AT1 selective antagonist having stronger in vivo potency than losartan. © 2011 Elsevier Ltd. All rights reserved.


Ryu S.,Kyung Hee University | Shin J.-S.,Kyung Hee University | Cho Y.-W.,Kyung Hee University | Kim H.K.,Boryung Pharm. Co. | And 5 more authors.
Biological and Pharmaceutical Bulletin | Year: 2013

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-κ) and activator protein-1 (AP-1). These reductions were accompanied by parallel reductions in the nuclear translocation of NF-κ and AP-1. Taken together, our data suggest that fimasartan down-regulates the expression of the iNOS in macrophages via NF-κ and AP-1 inactivation. © 2013 The Pharmaceutical Society of Japan.


Jeong E.-S.,Inje University | Kim Y.-W.,Inje University | Kim H.-J.,Inje University | Shin H.-J.,Inje University | And 5 more authors.
Xenobiotica | Year: 2014

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. © 2015 Informa UK Ltd. All rights reserved: reproduction in whole or part not permitted.


Choi H.-E.,Kyung Hee University | Yoo M.-S.,Kyung Hee University | Choi J.-H.,Kyung Hee University | Lee J.Y.,Kyung Hee University | And 8 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

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. © 2011 Elsevier Ltd. All rights reserved.


Chi Y.H.,Boryung Pharm. Co. | Lee H.,University of California at San Francisco | Lee H.,University of Washington | Paik S.H.,Boryung Pharm. Co. | And 5 more authors.
American Journal of Cardiovascular Drugs | Year: 2011

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. Subjects receiving fimasartan 240mg also received the same treatment in the fed state after an interval of 7 days. In another study, oral tablet doses of fimasartan 120 and 360mg or placebo were given once daily for 7 days to groups of eight fasted healthy male subjects (aged 20-55 years) in a double-blind, randomized, sequential-group design. Safety and tolerability were assessed. The PK and PD of fimasartan were also evaluated and compared for the different doses. Results: Fimasartan was safe and well tolerated, but with an increased incidence of low BP and postural dizziness for the 360mg dose after repeated administration. Fimasartan produced increases in plasma renin activity, angiotensin I and II, which were not dose dependent. Maximal increases occurred between 6 and 8 hours post-dose, lasting up to 48 hours. Fimasartan was absorbed rapidly after all doses and had a multiphasic distribution. Two peaks in the plasma concentration-time profile were observed in most subjects. Steady state was achieved after three doses, and accumulation was minimal after repeated doses for 7 days (24-30%). The effective half-life ranged from 9.84 to 13.2 hours. The systemic exposure of fimasartan was dose proportional, and no marked food effect was noted after administration of 240mg in the fed state. Urinary excretion of fimasartan was very low (1.74-2.51%), suggesting non-renal elimination. Conclusion: Fimasartan had a good safety profile and was well tolerated after fasted single oral doses of 20-480 mg, a fed single oral dose of 240 mg, and fasted repeated oral doses of 120 and 360mg in healthy subjects. In addition, the PK and PD of fimasartan in this population were well characterized. Further studies are needed to evaluate the safety, efficacy, and dose-response relationship of fimasartan in patients. with hypertension. © 2011 Adis Data Information BV. All rights reserved.


Yeong Park J.,Kyung Hee University | Woo Choi H.,Kyung Hee University | Li Choi D.,Kyung Hee University | Jeong Jang S.,Kyung Hee University | And 6 more authors.
Bulletin of the Korean Chemical Society | Year: 2013

Two piperazine-containing 3,4-dihyroquinazolines (BK10007S/8S) have been synthesized, based on our previous work on the synthesis and antitumoral activity of 3,4-dihyroquinazolines. After evaluating them for T-type calcium channel blocking effect and in vitro anti-cancer effect, they were profiled for acute and repeat dose toxicity (40 mg/kg, 2 weeks) to BALB/c mice. BK10007S/8S were further in vivo evaluated against human pancreatic MIA PaCa-2 carcinoma in BALB/cnu/nu nude mice, which exhibited 54 and 61% tumor growth inhibition through 57-day oral administration of 2 mg/kg of body weight, respectively.


PubMed | Boryung Pharm. Co.
Type: Clinical Trial, Phase I | Journal: American journal of cardiovascular drugs : drugs, devices, and other interventions | Year: 2011

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.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. Subjects receiving fimasartan 240 mg also received the same treatment in the fed state after an interval of 7 days. In another study, oral tablet doses of fimasartan 120 and 360 mg or placebo were given once daily for 7 days to groups of eight fasted healthy male subjects (aged 20-55 years) in a double-blind, randomized, sequential-group design. Safety and tolerability were assessed. The PK and PD of fimasartan were also evaluated and compared for the different doses.Fimasartan was safe and well tolerated, but with an increased incidence of low BP and postural dizziness for the 360 mg dose after repeated administration. Fimasartan produced increases in plasma renin activity, angiotensin I and II, which were not dose dependent. Maximal increases occurred between 6 and 8 hours post-dose, lasting up to 48 hours. Fimasartan was absorbed rapidly after all doses and had a multiphasic distribution. Two peaks in the plasma concentration-time profile were observed in most subjects. Steady state was achieved after three doses, and accumulation was minimal after repeated doses for 7 days (24-30%). The effective half-life ranged from 9.84 to 13.2 hours. The systemic exposure of fimasartan was dose proportional, and no marked food effect was noted after administration of 240 mg in the fed state. Urinary excretion of fimasartan was very low (1.74-2.51%), suggesting non-renal elimination.Fimasartan had a good safety profile and was well tolerated after fasted single oral doses of 20-480 mg, a fed single oral dose of 240 mg, and fasted repeated oral doses of 120 and 360 mg in healthy subjects. In addition, the PK and PD of fimasartan in this population were well characterized. Further studies are needed to evaluate the safety, efficacy, and dose-response relationship of fimasartan in patients with hypertension.


PubMed | f AB SCIEX, Korea University, Inje University, Chungbuk National University and 4 more.
Type: Clinical Trial | Journal: Xenobiotica; the fate of foreign compounds in biological systems | Year: 2016

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 53.3min 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 120mg 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.

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