• Archives of Pharmacal Research
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• v.26 no.7
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• pp.526-531
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• 2003

KR-31378 is a new drug candidate intended for the use in the prevention of ischemia-reperfusion damage. The objective of this preformulation study was to determine the physicochemical properties of KR-31378. The n-octanol to water partition coefficients of KR-31378 were 0.0504 at pH 3 and 0.8874 at pH 10. Accelerated stability of KR-31378 in solution and solid state was studied at 5, 40, $60^{\circ}C$. The stability testing indicated that the t90 for the drug in solid was estimated to be 2 years and 128.6 days at $25^{\circ}C$, while the that in aquesou solution was 68.6 days at $25^{\circ}C$. The KR-31378 was also found to be unstable under the relative humidity of 76%, probably because of the hygroscopic nature of the drug. In order to study compatibility of KR-31378 with typical excipients, potential change in differential scanning calorimetry spectrum was studied in 1:1 binary mixtures of KR-31378 and Aerosil, Avicel, Eudragit, lactose, PEG, talc, CMC, PVP, starch. As a result, CMC, PVP, and starch were found to be incompatible with KR-31378, indicating the addition of these excipients may complicate the manufacturing of the formulation for the drug. Particle size distribution of KR-31378 powder was in the size range of 9-93 $\mu$ m with the mean particle size of 37.9 $\mu$ m. The flowability of KR-31378 was apparently inadequate, indicating the granulation may be necessary for the processing of the drug to solid dosage forms. Crystallization of the drug with a number of organic solvents did not lead a crystalline polymorphism. In addition, dissolution of the drug from the powder was adequately rapid at $37^{\circ}C$ in water.

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.5
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• pp.381-388
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• 2001

This work describes the pharmacological inhibition by KR 31378 and its acetyl metabolite, KR 31612, of the apoptotic cell death induced by $H_2O_2$ in the A7r5 cells. Exposure of A7r5 cells to $H_2O_2$ (0.5 mM) induced a concentration-dependent cytotoxicity in association with oligonucleosomal DNA fragmentation. $H_2O_2-induced$ cell death was potently suppressed by KR 31378, KR 31612, ${\alpha}-tocopherol$ or trolox. Additionally, the apoptotic death of A7r5 cells (DNA ladders on electrophoresis) was also strongly suppressed by KR 31378 and KR 31612, but to a less degree by ${\alpha}-tocopherol$ and trolox. As a mechanistic study, incubation with $H_2O_2$ markedly showed a decreased Bcl-2 level and, in contrast, increased Bax protein and cytochrome C release, which were significantly and concentration-dependently reversed by KR 31378 and KR 31612 as well as by ${\alpha}-tocopherol$ and trolox. KR 31378 and ${\alpha}-tocopherol$ significantly reduced lipid peroxidation in accordance with reduced intracellular ROS and peroxyl radical. These results suggest that KR 31378 has a therapeutic potential against the apoptotic injury via mediation of anti- oxidative stress.

• YAKHAK HOEJI
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• v.41 no.1
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• pp.117-125
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• 1997

The pharmacological effects of benzopyran potassium channel openers (lemakalim, KR-30450 and KR-30818) on the occlusion/reperfusion-induced myocardial infarction were investigat ed. In anesthetized rats, subjected to 45-min occlusion of the left anterior descending coronary artery (LAD) followed by 90-min reperfusion, the infarct size was measured by calculating the ratio of infarct zone to area at risk (IZ/AAR) with the Evans blue/TTC technique. Rats were intravenously given vehicle (1% DMSO), lemakalim, KR-30450, and KR-30818 alone or in combination with a selective K$_{ATP}$ blacker glibenclamide, 30 min prior to coronary occlusion. Compared to vehicle, lemakalim (30 ${\mu}$g/kg i.v.), the active enantiomer of cromakalim, had a tendancy to decrease infarct size. KR-30450(30 ${\mu}$g/kg, i.v.). the newly synthetized potassium channel openers (PCOs), caused a reduction of infarct size (from 70${\pm}$4%to 57${\pm}$5%). but KR-30818 (30 ${\mu}$g/kg, i.v.), a metabolite of KR-30450. did not modify infarct size. It seem ed likely that glibenclamide (0.3mg/kg, i.v.), given in combination, reduced the effects of these PCOs, especially KR-30450 (30 ${\mu}$g/kg, i.v.) on the infarct size. These results indicate that. in the coronary occluded rat model of ischemia, lemakalim and KR-30450 may exert cardioprotective activity through a reduction of infarct size, the effect being considered related to the opening of K$_{ATP}$ channel.

• Korean Journal of Veterinary Research
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• v.40 no.4
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• pp.741-746
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• 2000

We have developed a rapid, simple and precise high-performance liquid chromatographic (HPLC) method using an UV detection system for the determination of new anti-HIV candidates, nineteen KR-V compounds, in rat plasma. We used a analytical columnn of $C_{18}$ ($5{\mu}m$, $250{\times}2.0mm$ I.D.) and a mobile phase of water and ACN mixture (40/60, v/v). Under these conditions, all the KR-V compounds were readily separated from plasma with retention times of 4-12 min. The limits of quantitation for the 19 KR-V compounds were 15-30 ng/ml. The recoveries from the plasma were higher than 85% (C.V.<10%) with exception of KR-V 2, 7 and 15. The compounds KR-V 2, 7 and 15, containing ester moieties, were found to be unstable in plasma. This result suggests that esters, like KR -V 2, 7 and 15, should be excluded from future structure design studies of anti-HIV KR-V agents. In conclusion, the current HPLC method is a valuable analytical tool for investigating the pharmacokinetics of the KR-V series in rats.

• Journal of Life Science
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• v.20 no.7
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• pp.969-976
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• 2010

In vivo studies of KR-31125 (2-butyl-5-dimethoxymethyl-6-phenyl-7-methyl-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine) were performed in pithed rats, conscious angiotensin II (AII) challenged normotensive rats, renal hypertensive rats (RHRs) and furosemide-treated beagle dogs. KR-31125 induced a non-parallel right shift in the dose-pressor response curve to AII ($ID_{50}$: 0.095 mg/kg) with a dose-dependent reduction in the maximum responses in pithed rats. Compared to losartan, this antagonistic effect was about 18 times more potent, presenting competitive antagonism. Other agonists such as norepinephrine and vasopressin did not alter the responses induced by KR-31125. Orally administered KR-31125 had no agonistic effect and dose-dependently inhibited the pressor response to AII with a slightly weaker potency ($ID_{50}$: 0.25 and 0.47 mg/kg, respectively) in the AII-challenged normotensive rat model, but with a more rapid onset of action than losartan (time to $E_{max}$: 30 min for KR-31125 and 6 hr for losartan). KR-31125 produced a dose-dependent antihypertensive effect with a higher potency than losartan in RHRs, and these effects were confirmed in furosemide-treated dogs where they presented a dose-dependent and long-lasting (>8 hr) antihypertensive effect with a rapid onset of action (time to $E_{max}$: 2-4 hr), as well as a 20-fold greater potency than losartan. These results suggest that KR-31125 is a potent, orally active $AT_1$ receptor antagonist that can be applied to the development of new diagnostic and research tools as an added exploratory potential of $AT_1$ receptor antagonist.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1996.04a
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• pp.252-252
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• 1996

We Investigated the peripheral excitatory effect of capsaicin and KR-25018, a newly synthesized capsaicin derivative which was demonstrated to have a potent analgesic activity. KR-25018 and capsaicin were found to be both potent efficacious contractors of isolated guinea pig bronchial smooth muscle. KR-25018 was equipotent with capsaicin and [Sar$\^$9/,Met(O$_2$)$\^$11/]-substance P, 10-fold more potent than histamine and 10-fold less potent than (${\beta}$ -Ala$\^$8/)-neurokinin A(4-10), and their -log(M)EC$\_$50/ values were 6.94${\pm}$0.08, 6.86${\pm}$0.05, 6.96${\pm}$0.07, 5.64${\pm}$0.04, 7.96${\pm}$0.02, respectively. Contractile responses to KR-25018 and capsaicin were potentiated by phosphoramidon (1 ${\mu}$M), an inhibitor of neuropeptide-inactivating endopeptidase, but completely abolished in a calcium-free medium. These responses to KR-25018 and capsaicin were unaffected by the NK-1 antagonist CP96345 (1${\mu}$M), partially inhibited by the NK-2 antagonist SR48968 (1 ${\mu}$M) but almost completely abolished by a combination of the antagonists. A vanilloid receptor antagonist capsazepine competitively antagonized the responses to both KR-25018 and capsaicin (pA$_2$: aganst KR-25018, 5.98${\pm}$0.47; against capsaicin, 5.80${\pm}$0.31), and a capsaicin-sensitive cation channel antagonist ruthenium red caused significant reduction in the maximum responses to KR-25018 and capsaicin (pD'$_2$: against KR-25018, 4.61${\pm}$0.33; against capsaicin 4.96${\pm}$0.21). In conclusion, the present results suggest that KR-25018 and cpasaicin act on the same vanilloid receptor inducing the influx of calcium through ruthenium red-sensitive cation channel and produce contractile responses via the release of tachykinins that act on both NK-1 and NK-2 receptor subtypes.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1993.04a
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• pp.130-130
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• 1993

실험목적: KR 53170 및 KR 53234 는 천연물에서 분리 추출한 화합물로 terpene lacton ring을 가진 약산성 물질이다. in vitro 항종양 실험에서 종양억제효과가 있었고 in vivo 항종양 실험에서도 유의성 있는 효과가 있었으며 급성 경구독성시험에서도 독성이 낮은 것으로 평가 되었다. 이에 따라 KR 53170 등의 약물동태학적인 성질을 연구하여 독성실험과 임상실험을 위한 용법용량을 결정하고 나아가 본약물의 제제개발에 도움이 되도록 본 연구를 시행하였다. 방법: KR 53170 및 53234은 경구시 20mg/kg, 정맥투여시는 10mg/kg로 투여하였다. Rat의 혈장 sample 채취는 ether로 흡입마취 시킨 후 heart puncture 하였다. 뇨시료는 대사 cage를 이용하여 채취하였으며 얻어진 모든 시료는 HPLC로 분석 하였다. 분석결과는 computer program 'Multi-free'를 이용하여 주요 pqarameter를 산출하였다. 인체혈액에 대한 혈청단백결합율 측정은 ultrafiltration법을 이용하였다. 즉 YMT membrane을 이용하여주요 parameter를 산출하였다. 인체혈액에 대한 혈청단백결합율 측정은 ultrafiltration법을 이용하였다. 즉 YMT membrane을 이용하여 유리약물을 분리하여 HPLC로 정량하였다. 결과 및 고찰: 1. KR 53170 10mg/kg 정맥투여시 최고혈중농도는 0.55ug/ml, 반감기는 0.51hr, 분포용적은 4.5L이었다. 20mg/kg를 경구 투여시 최고 혈중농도는 0.18ug/ml, 반감기는 3.5기산이고 AUC는 0.91ug.ml, 분포용적 28Lm, Ka 3.49$hr^{－1}$ 그리고 Cl는 5.5L/hr/kg이었다. 이는 투여용량에 비해 매우 적은량이 흡수되고 배설 된 것으로 약물이 혈액에 대한 용해도 문제에 기인하는 것으로 간주된다. 2. KR 53234 10mg/kg 정맥투여후의 최고혈중농도는 1.14ug/ml, 반감기는 0.50hr, 분포용적은 2.2L이었다. 20mg/kg 경구 투여시의 최소 혈중 농도는 0.33 ug/ml, 소실반감기는 1.5시간, AUC는 0.942ug.hr/ml, 분포용적 11L, Ka는 3.05 $hr^{－1}$ 그리고 Cl는 5.3L/hr/kg이었다. 이는 KR 53170에서와 같이 매우 적은량이 흡수되고 배설되었다. 3. KR 53170의 혈청단백 결합율은 5-500 ug/ml 범위에서 78.7-86.2%이었고 KR 53234의 혈청단백결합율은 5-100 ug/ml 범위에서 79.6-71.2%이었다.이었다.

• Journal of Microbiology and Biotechnology
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• v.27 no.7
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• pp.1336-1344
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• 2017

Hepatitis B virus (HBV) is a major cause of liver cirrhosis and hepatocellular carcinoma. With recent identification of HBV receptor, inhibition of virus entry has become a promising concept in the development of new antiviral drugs. To date, 10 HBV genotypes (A-J) have been defined. We previously generated two murine anti-preS1 monoclonal antibodies (mAbs), KR359 and KR127, that recognize amino acids (aa) 19-26 and 37-45, respectively, in the receptor binding site (aa 13-58, genotype C). Each mAb exhibited virus neutralizing activity in vitro, and a humanized version of KR127 effectively neutralized HBV infection in chimpanzees. In the present study, we constructed a humanized version (HzKR359-1) of KR359 whose antigen binding activity is 4.4-fold higher than that of KR359, as assessed by competitive ELISA, and produced recombinant preS1 antigens (aa 1-60) of different genotypes to investigate the binding capacities of HzKR359-1 and a humanized version (HzKR127-3.2) of KR127 to the 10 HBV genotypes. The results indicate that HzKR359-1 can bind to five genotypes (A, B, C, H, and J), and HzKR127-3.2 can also bind to five genotypes (A, C, D, G, and I). The combination of these two antibodies can bind to eight genotypes (A-D, G-J), and to genotype C additively. Considering that genotypes A-D are common, whereas genotypes E and F are occasionally represented in small patient population, the combination of these two antibodies might block the entry of most virus genotypes and thus broadly neutralize HBV infection.

• Journal of the Korean Society of Food Science and Nutrition
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• v.30 no.5
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• pp.765-769
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• 2001

Starches of flavored glutinous rice were analyzed by using scanning electron microscope (SEM) and differential scanning calorimetry (DSC) and tested on the starch granule susceptibility to 15% H$_2$SO$_4$, glucoamylase and $\alpha$-amylase. The shape of starch granules form flavored glutinous rice varieties was polygonal and the size was 4~6 $\mu$m in diameter. According to DSC, glutinous rice starch showed onset temperature (T$_{o}$) range 59.8~62.5$^{\circ}C$ and KR92021-B-B-42-3-B and KR92021-B-B-165-1-B showed higher enthalpy ($\Delta$H) on gelatinization than others. The starches from KR92021-B-B-5-2-B and KR92021-B-B-42-3-B showed lower hydrolysis rate using 15% H$_2$SO$_4$ than KR92021-B-B-165-1-B. KR92021-B-B-5-2-B showed higher degree of hydrolysis of glucoamylase and $\alpha$-amylase than the others.

• YAKHAK HOEJI
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• v.59 no.2
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• pp.59-65
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• 2015

KR-67500, trans-4-(2-(4-methyl-1,1-dioxido-6-(2,4,6-trichlorophenyl)-1,2,6-thiadiazinan-2-yl)acetamido)adamantane-1-carboxamide, is a novel $11{\beta}$-HSD1 inhibitor with its therapeutic effects of its anti-diabetic, anti-adipogenic and anti-osteoporotic activity. This study was performed to evaluate in vitro and in vivo pharmacokinetic properties of KR-67500 as a new drug candidate. KR-67500 was stable and highly bound to proteins in rat plasma. The microsomal stabilities of KR-67500 in human and rat liver were high. The inhibitory effect of KR-67500 for five cytochrome P450 enzymes was low. Preclinical pharmacokinetic studies have been carried out with intravenous or oral administrations of KR-67500 (10 mg/kg) to male rats and monkey. KR-67500 showed low clearance (0.68 l/h/kg) and high oral bioavailability (102%) in male rats. These results suggest that KR-67500 has good drug-like pharmacokinetic properties with a low first-pass effect and high bioavailability for an oral therapeutic agent of diabetes and osteoporosis.