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Hye-Eun Choi,
Jung-Hye Choi,
Jae Yeol Lee,
Je Hak Kim,
Ji Han Kim,
Joon Kwang Lee,
Gyu Il Kim,
Yong Park, Yong Ha Chi,
Soo Heui Paik,
Joo Han Lee,
Kyung-Tae Lee
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ABSTRACT: 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 10-100nM. 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.
Bioorganic & medicinal chemistry letters 02/2013; · 2.65 Impact Factor
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ABSTRACT: 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.
Biological & Pharmaceutical Bulletin 01/2013; 36(3):467-74. · 1.66 Impact Factor
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ABSTRACT: 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.
Archives of Pharmacal Research 07/2012; 35(7):1123-6. · 1.59 Impact Factor
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ABSTRACT: 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)=0.42 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 AT(1) selective antagonist having stronger in vivo potency than losartan.
Bioorganic & medicinal chemistry letters 02/2012; 22(4):1649-54. · 2.65 Impact Factor
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ABSTRACT: 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.
American Journal of Cardiovascular Drugs 10/2011; 11(5):335-46. · 1.77 Impact Factor
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Yong Ha Chi,,
Howard Lee,
Soo Heui Paik,,
Joo Han Lee,,
Byoung Wook Yoo,,
Ji Han Kim,,
Hyun Kwang Tan,,
Sang Lin Kim,
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ABSTRACT: 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 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.Results 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.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 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.
American Journal of Cardiovascular Drugs 09/2011; 11(5):335-346. · 1.77 Impact Factor
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Hye-Eun Choi,
Min-Sang Yoo,
Jung-Hye Choi,
Jae Yeol Lee,
Je Hak Kim,
Ji Han Kim,
Joon Kwang Lee,
Gyu Il Kim,
Yong Park, Yong Ha Chi,
Soo Heui Paik,
Joo Han Lee,
Kyung-Tae Lee
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ABSTRACT: 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.
Bioorganic & medicinal chemistry letters 09/2011; 21(21):6236-41. · 2.65 Impact Factor
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ABSTRACT: 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. The multiple reaction monitoring was based on the transition of m/z 502.1 → 207.1 for fimasartan, 486.2 → 207.1 for BR-A-557 and 526.1 → 207.1 for BR-A-563 (internal standard). The assay utilized a simple precipitation procedure with acetonitrile and isocratic elution. The LLOQ was 0.2 ng/mL for fimasartan and BR-A-557 using 50 μL plasma samples. The assay was linear over a concentration range from 0.2 to 500 ng/mL for fimasartan and BR-A-557, with correlation coefficients >0.9995. The intra- and inter-day assay accuracies were 93.6–108.0 and 90.8–101.4% for fimasartan and 102.2–107.1 and 99.6–103.3% for BR-A-557, respectively. The intra- and inter-day precision were 2.4–4.4 and 3.0–13.4% for fimasartan and 3.1–5.2 and 2.8–9.8% for BR-A-557, respectively. The developed assay may be used to study the metabolism and mechanistic pharmacokinetics of fimasartan in future studies. Copyright © 2011 John Wiley & Sons, Ltd.
Biomedical Chromatography 01/2011; 25(11):1208 - 1214. · 1.97 Impact Factor
