• 약학회지
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• 제58권1호
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• pp.16-20
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• 2014

KR-31064 was developed for the strong angiotensin II receptor antagonist among the one of pyridyl imidazol series compounds. To investigate the receptor-ligand binding characteristics of this nonpeptide antagonist, binding experiments were deployed in various conditions and ex vivo contractile responses were tested toward the standard compound, losartan. Receptor binding experiments with radiolabeled angiotensin II, the $IC_{50}$ value for KR-31064 resulted 0.67 nM without any activities toward type 2 angiotensin II receptor. The comparative potency against losartan was more than 18 fold and the specific activity in type 1 angiotensin II receptor was more than 10,000 fold comparing to the type 2 receptor. Scatchard analysis of saturation binding data showed KR-31064 acted on the receptor in a competitive mode. KR-31064 inhibited the contractile response derived by angiotensin II ($pK_B$: 9.86) similar to that of losartan with decreased maximum signals. As a potent and specific type 1 angiotensin II receptor antagonist, KR-31064 may have possibilities for the development of diagnostic ligands that can be used as tools for various biochemical research experiments and non-invasive diagnostics.

• Archives of Pharmacal Research
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• 제19권5호
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• pp.390-395
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• 1996

To investigate whether $AT_{1}$ receptor antagonists are acting by increasing endothelium-de-pendent and -independent relaxation of aortas in normotensive rats, $AT_{1}$ receptor antagonists, losartan and KR-30988, and angiotensin converting enzyme inhibitor, captopril, were orally administered for two weeks (50 mg/kg, b.i.d.). THe blood pressure, heart rate and body weight were not significantly changed by losartan, KR-30988 and captopril compared to the control group. In aortic preparations, the $pD_{2}$ of KR-30988 for ACh-induced relaxation was 8.33 $\pm$ 0.16, significantly (p <0.05) lower than that of control group $(7.71 \pm 0.15)$. ACh-induced relaxation was significantly increased on losartan-treated group (p<0.01) at $10^{-6}$ M of ACh, and in captopril-treated group (p<0.05) at the range of $10^{-7}$ -$10^{-5}$ M of ACh. The $pD_{2}$ values for histamine-induced relaxatio of losartan, KR-30988 and captopril were 5.57 $\pm$ 0.10, 5.85 $\pm$ 0.21 and 5.60 $\pm$ 0.01, respectively, with significant differences in all groups (p<0.01) compared to that of control group (5.13 $\pm$ 0.09). ACh-induced relaxations of aortic preparations were not changed by pretreatment of indomethacin ($10_{-5}$ M), and completely bolcked by pretreatment of L-NAME $(10_{-5}M)$ in all groups. Sodium nitroprusside-induced relaxations were not significantly changed by all drugs tested in this experiments. These results suggest that $AT_{1}$ receptor antagonists, losartan and KR-30988, enhance the endothelium-dependent relaxatio on aortic preparations through the release of, or increase sensitivity, to nitric oxide in nor-motensive rats.

• Journal of Pharmaceutical Investigation
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• 제40권1호
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• pp.51-57
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• 2010

Losartan potassium, 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol mono-potassium salt, is a new class of antihypertensive agents, and is an antagonist in angiotensin receptor. The purpose of the present study was to evaluate the bioequivalence of two Losartan potassium tablets, Cozaar tablet (MSD Pharmaceutical Co., Ltd.) and Losata tablet (Kyung Dong Pharmaceutical Co., Ltd.), according to the guidelines of the Korea Food and Drug Administration (KFDA). The release of losartan from the two losartan potassium formulations in vitro was tested using KP VIII Apparatus II method with various dissolution media. Twenty eight healthy male subjects, $23.86{\pm}1.80$ years in age and $67.27{\pm}6.60\;kg$ in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After a single tablet containing 50 mg as losartan potassium was orally administered, blood samples were taken at predetermined time intervals, and the concentrations of losartan in serum were determined using HPLC with fluorescence detector. The dissolution profiles of two formulations were similar in all tested dissolution media. The pharmacokinetic parameters such as $AUC_t$, $C_{max}$ and $T_{max}$ were calculated, and Equiv Test/K-BE Test 2002 was utilized for the statistical analysis of the parameters using logarithmically transformed $AUC_t$, $C_{max}$ and untransformed $T_{max}$. The results showed that the differences between two formulations based on the reference drug, Cozaar, were -2.70%, 1.45% and 2.31% for $AUC_t$, $C_{max}$ and $T_{max}$, respectively. There were no sequence effects between two formulations in these parameters. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of log 0.8 to log 1.25 (e.g., log 0.8852~log 1.0655 and log 0.8319~log 1.2342 for $AUC_t$ and $C_{max}$, respectively). Thus, the criteria of the KFDA bioequivalence guideline were satisfied, indicating Losata tablet was bioequivalent to Cozaar tablet.

• Childhood Kidney Diseases
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• 제27권2호
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• pp.97-104
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• 2023

Purpose: Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) are frequently employed to counteract the detrimental effects of proteinuria on glomerular diseases. However, the effects of ARBs remain poorly examined in pediatric patients with immunoglobulin A (IgA) nephropathy. Herein, we evaluated the efficacy and safety of losartan, an ARB, in pediatric IgA nephropathy with proteinuria. Methods: This prospective, single-arm, multicenter study included children with IgA nephropathy exhibiting proteinuria. Changes in proteinuria, blood pressure, and kidney function were prospectively evaluated before and 4 and 24 weeks after losartan administration. The primary endpoint was the difference in proteinuria between baseline and 24 weeks. Results: In total, 29 patients were enrolled and received losartan treatment. The full analysis set included 28 patients who received losartan at least once and had pre- and post-urinary protein to creatinine ratio measurements (n=28). The per-protocol analysis group included 22 patients who completed all scheduled visits without any serious violations during the study period. In both groups, the mean log (urine protein to creatinine ratio) value decreased significantly at 6 months. After 24 weeks, the urinary protein to creatinine ratio decreased by more than 50% in approximately 40% of the patients. The glomerular filtration rate was not significantly altered during the observation period. Conclusions: Losartan decreased proteinuria without decreasing kidney function in patients with IgA nephropathy over 24 weeks. Losartan could be safely employed to reduce proteinuria in this patient population. ClinicalTrials.gov trial registration (NCT0223277)

• Biomolecules & Therapeutics
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• 제28권1호
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• pp.98-103
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• 2020

Marfan syndrome (MFS), a connective tissue disorder caused by mutations in the fibrillin-1 (Fbn1) gene, has vascular manifestations including aortic aneurysm, dissection, and rupture. Its vascular pathogenesis is assumed to be attributed to increased transforming growth factor β (TGFβ) signaling and blockade of excessive TGFβ signaling has been thought to prevent dissection and aneurysm formation. Here, we investigated whether galunisertib, a potent small-molecule inhibitor of TGFβ receptor I (TβRI), attenuates aneurysmal disease in a murine model of MFS (Fbn1^C1039G/+) and compared the impact of galuninsertib on the MFS-related vascular pathogenesis with that of losartan, a prophylactic agent routinely used for patients with MFS. Fbn1^C1039G/+ mice were administered galunisertib or losartan for 8 weeks, and their ascending aortas were assessed for histopathological changes and phosphorylation of Smad2 and extracellular signal-regulated kinase 1/2 (Erk1/2). Mice treated with galunisertib or losartan barely exhibited phosphorylated Smad2, suggesting that both drugs effectively blocked overactivated canonical TGFβ signaling in Fbn1^C1039G/+ mice. However, galunisertib treatment did not attenuate disrupted medial wall architecture and only partially decreased Erk1/2 phosphorylation, whereas losartan significantly inhibited MFS-associated aortopathy and markedly decreased Erk1/2 phosphorylation in Fbn1^C1039G/+ mice. These data unexpectedly revealed that galunisertib, a TβRI inhibitor, showed no benefits in aneurysmal disease in MFS mice although it completely blocked Smad2 phosphorylation. The significant losartan-induced inhibition of both aortic vascular pathogenesis and Smad2 phosphorylation implied that canonical TGFβ signaling might not prominently drive aneurysmal diseases in MFS mice.

• The Korean Journal of Physiology
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• 제27권2호
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• pp.217-225
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• 1993

The role of endogenous brain angiotensin ll (Ang ll) in mediating the cardiovascular and vasopressin responses to hemorrhage was assessed in conscious spontaneously hypertensive rats (SHR), and normotensive Wistar-Kyoto (WKY) rats. Artificial cerebrospinal fluid (aCSF) with or without losartan (DuP 753), a specific Ang ll receptor subtype I $(AT_1)$ antagonist and saralasin, a combined $AT_1/AT_2$ antagonist was administered into the cerebral lateral ventricle. Hemorrhage was performed at a rate of 3 ml/kg/min far 5 min. Intracerebroventricular administration of losartan and saralasin had no effect on the basal blood pressure. However, in response to acute hemorrhage, central Ang ll antagonists produced a remarkably greater fall in blood pressure, a reduced tachycardia, and an enhanced renin release compared with the aCSF control experiment in SHR, but effected no significant change in WKY rats. Central Ang ll-blocked SHR showed significantly lower blood pressure and heart rate during the recovery period than the aCSF control rats. Vasopressin release tallowing the hemorrhage was attenuated by icv Ang ll antagonists: the effect was more pronounced in SHR than in WKY rats. Centrally administered losartan and saralasin produced remarkably similar effects on the cardiovascular function and vasopressin responses to hemorrhage. These data suggest that brain Ang ll acting primarily through AT, receptors plays an important physiological role in mediating rapid cardiovascular regulation and vasopressin release in response to hemorrhage especially in Hypertensive rats.

• Archives of Pharmacal Research
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• 제17권4호
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• pp.263-268
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• 1994

This study was conducted to characterize the in vivo pharmacology of KR-30988, KR-30992 and losartan, new AT antagonists, given as i.v. cumulative doses, in two antimal models of high renin, conscious renal artery-ligated hypertensinve rats (RHRs) and nomotensive rats anesthetized with urethane (90 mg/kg, i.p.) and .alpha.-chloralose (90 mg/kg, i.p.), with a special emphasis on the phamacological characterization of the latter model. In conscious RHRs, KR-30988, KR-30992, losartan and captopril caused a dose-dependent decrease in blood pressure, their relative potencise ($ED_{20}$) being 0.057, 0.028, 0164 and 0.018 mg/kg, i.v., repectively. In anesthetized rats, 2 hours after anesthesia, plasma renin activity was increased from 7.31 tp 34.07 ng/ml/h, the level approximately 1.5 times greater than the highest level in RHRs. In anesthtized rats, the $ED_{20}$s for all four compounds were 0.004 mg/kg i.v., respectively. By comparison, $ED_{20}$sfrom anesthetized rats were 4 to 5 times smaller than those from conscious RHRs, with a good correlation (.gamma. = 0.999) noted between thetized rats to the hypotensive activity of the compounds and the same order of potencies intwo models. These results suggest that, in addition to PHRs, the normotensive rats anesthetized as above can serve as a suitable model for the rapid phamacological evaluation of $AT_1$ receptor antagonists.

• 생명과학회지
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• 제20권7호
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• pp.969-976
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• 2010

피리딜 이미다졸 시리즈의 비펩타이드 안지오텐신 수용체 리간드로 새롭게 개발된 KR-31125에 대한 생체 내활성을 동물모델에서 검증하였다. 척수장애 동물모델에서 KR-31125는 비대칭 농도의존적으로 로자탄보다 18배 이상의 경쟁적인 혈압강하 효과를 나타내었으며, 기타 수용체 촉진제들의 영향을 받지 않았다. 안지오텐신으로 유도된 정상혈압 쥐모델에서는 대조화합물인 로자탄과 비교하여 경구효과는 동등하였으나 더 빠른 초기효과가 관찰되었다. 또한 신성고혈압 쥐모델에서 KR-31125는 로자탄보다 3배 이상의 지속형 혈압강하 효과를 나타내었고, 이뇨제를 투여하여 레닌을 활성화시킨 개실험 모델에서 KR-31125는 로자탄보다 20배 이상의 지속적인 경구혈압강하 효과를 나타내었다. 이러한 KR-31125의 생체 내 활성특징은 대사물질을 통하여 효과를 발휘하는 로자탄과 달리 동일물질의 효과에 의한 것으로 고혈압 및 혈관질환과 깊은 관련이 있는 안지오텐신 조절시스템에 대한 세포영상, 비침투성 진단등의 도구물질로서 가능성이 높을 것으로 판단된다.

• 한국임상약학회지
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• 제7권2호
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• pp.91-95
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• 1997

• 생명과학회지
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• 제18권7호
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• pp.918-923
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• 2008

안지오텐신II 수용체(AT1 수용체)는 혈관수축과 체내 전해질이온 조절에 중요한 역할을 한다. AT1 수용체 길항제(ARB)는 고혈압 치료에 이용되며 최근에는 당뇨병을 포함한 대사질환에 효능이 있음이 알려져 있다. 이 연구에서는 ARB 처리 후 세포 내 인산화단백질에 인산화가 일어나는지를 antibody array를 이용하여 실험하였다. 아미노산세린 및 트레오닌에 인산화되는 단백질 6개, 티로신에 인산화되는 단백질 12개에 대한 항체를 선정하여 nitrocellulose membrane에 부착시켰다. AT1 수용체를 발현한 COS-1 세포에 로사틴(losartan)을 처리하였을 때 small GTPase인 RhoA의 세린 잔기에 인산화가 20% 증가함을 관찰하였다. RhoA는 세포골격의 재배열에 중요한 역할을 하며 세린 잔기에 인산화가 되면 활성이 억제된다. 본 연구결과로부터 ARB가 AT1 수용체에 의한 혈관수축을 억제할 뿐만 아니라 새로운 세포 신호룰 생성함을 알 수 있다.