Drug design and discovery最新文献_第6页

Symmetric covalent linkage of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) results in novel derivatives with increased inhibitory activities against calcium/calmodulin complex. N-(6-氨基己基)-5-氯-1-萘磺酰胺(W-7)的对称共价键导致对钙/钙调素复合物具有增强抑制活性的新型衍生物。

Drug design and discovery Pub Date : 1999-11-01

H Yokokura, M Osawa, T Inoue, I Umezawa, Y Naito, M Ikura, H Hidaka

{"title":"Symmetric covalent linkage of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) results in novel derivatives with increased inhibitory activities against calcium/calmodulin complex.","authors":"H Yokokura, M Osawa, T Inoue, I Umezawa, Y Naito, M Ikura, H Hidaka","doi":"","DOIUrl":"","url":null,"abstract":"A useful calmodulin (CaM) antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), was invented by Hidaka et al. in 1978 (J. Pharmacol. Exp. Ther. 207, 8-15). Here, we have designed new CaM antagonists on the basis of the three-dimensional structure of Ca2+/CaM complexed with W-7. Eleven new compounds all share a similar architecture, in which two W-7 molecules are linked between their aminohexyl termini by a linker with different functionalities. A wide range of inhibitory activities against Ca2+/CaM-dependent protein kinase I (CaM kinase I) has been observed with these self-crosslinked W-7 analogs, (W-7)2. In vitro competitive CaM kinase I assays using CaM kinase I and nuclear magnetic resonance studies indicated that one (W-7)2 molecule binds to one CaM molecule as expected, with the two chloronaphthalene rings of (W-7)2 being anchored separately to the N- and C-terminal hydrophobic pockets of Ca2+/CaM. The most potent compound, N,N'-bis[6-(5-chloro-1-naphthalenesulfonyl)-amino-1-hexyl]-p-xylen e-diamine ((W-7)2 - 10), inhibits CaM kinase I activity at an IC50 value of 0.23 microM; about 75 times more effectively than W-7. The length and basicity of the linker sequence in (W-7)2 significantly contribute to inhibitory activity. The present study opens an avenue for developing powerful CaM antagonists that could be used at low doses in vivo.","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 3","pages":"203-16"},"PeriodicalIF":0.0,"publicationDate":"1999-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21480743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis of combinatorial libraries of 3,4,5-trisubstituted 2(5H)-furanones. Part Two: Construction of a library of 4-amino-5-alkoxy-2(5H)-furanones. 3,4,5-三取代2(5H)-呋喃酮组合文库的合成。第二部分:4-氨基-5-烷氧基-2(5H)-呋喃酮文库的构建。

Drug design and discovery Pub Date : 1999-11-01

E Lattmann, D C Billington, C A Langley

引用次数: 0

Design and synthesis of stable, water soluble radicals as potential anti-cancer agents. 设计和合成稳定的水溶性自由基作为潜在的抗癌剂。

Drug design and discovery Pub Date : 1999-11-01

E Lattmann, A Begum, M J Plater

引用次数: 0

Use of the triazolotriazine [3H]ZM 241385 as a radioligand at recombinant human A2B adenosine receptors. 使用三唑三嗪[3H]ZM 241385 作为重组人 A2B 腺苷受体的放射性配体。

Drug design and discovery Pub Date : 1999-11-01

X D Ji, K A Jacobson

{"title":"Use of the triazolotriazine [3H]ZM 241385 as a radioligand at recombinant human A2B adenosine receptors.","authors":"X D Ji, K A Jacobson","doi":"","DOIUrl":"","url":null,"abstract":"Radiolabeled ZM 241385 (4-(2-[7-amino-2- ¿furyl¿¿1,2,4¿triazolo¿2,3-a¿¿1,3,5¿triazin-5-ylaminoethyl)p henol), has previously been used as a high affinity radioligand for the labeling of A2A adenosine receptors in cell membranes. Another subtype, the A2B receptor, is the least well-defined subtype of adenosine receptors and lacks selective pharmacological probes. In the present study, we have used [3H]ZM 241385 as a radioligand to label recombinant human A2B adenosine receptors in HEK-293 cell membranes, that do not express A2A adenosine receptors, and found that the pharmacological profile is consistent with the SAR of A2B receptors. Saturable, specific binding (Kd 33.6 nM, Bmax 4.48 pmol/mg protein) that was best described by a one-site model was found, and specific binding was approximately 75% of total binding. [3H]ZM 241385 binding was displaceable by a large number of compounds known to interact with A2B receptors; thus, this method has promise as a tool in the search for agonists and antagonists selective for this subtype. Xanthine analogs, which are antagonists, proved to be the most potent displacers. The Ki of XAC, xanthine amine congener, was 12.3 nM, while CPX (8-cyclopentyl-1,3-dipropylxanthine) was less potent. The non-selective triazoloquinazoline antagonist CGS 15943 (Ki 16.4 nM), which is similar in structure to ZM 241385, was slightly less potent than XAC. The non-xanthine A2B-antagonist alloxazine displaced [3H]ZM 241385-binding with a Ki of 462 nM, similar to its affinity in functional assays. Adenosine derivatives known to activate this receptor subtype, such as NECA (5'-N-ethylcarboxamidoadenosine) and R-PIA (N6-phenylisopropyladenosine), were considerably less potent than the 8-substituted xanthines examined.","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 3","pages":"217-26"},"PeriodicalIF":0.0,"publicationDate":"1999-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3425640/pdf/nihms-397633.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21480744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis and pharmacological activity of pyrazolopyrrolopyrimidine derivatives having vasorelaxing activity. 具有血管舒张活性的吡唑吡喃嘧啶衍生物的合成及药理活性。

Drug design and discovery Pub Date : 1999-08-01

T Kumagai, H Matsunaga, S Kaneda, H Shimizu, E Ebisawa, M Kitamura, T Suzuki, M Yuasa, Y Nagao

引用次数: 0

Structure-activity relationship of hydroxamate-based inhibitors on membrane-bound Fas ligand and TNF-alpha processing. 羟酸盐基膜结合Fas配体抑制剂与tnf - α加工的构效关系。

Drug design and discovery Pub Date : 1999-08-01

M Yamamoto, R Hirayama, K Naruse, K Yoshino, A Shimada, S Inoue, N Kayagaki, H Yagita, K Okumura, S Ikeda

{"title":"Structure-activity relationship of hydroxamate-based inhibitors on membrane-bound Fas ligand and TNF-alpha processing.","authors":"M Yamamoto, R Hirayama, K Naruse, K Yoshino, A Shimada, S Inoue, N Kayagaki, H Yagita, K Okumura, S Ikeda","doi":"","DOIUrl":"","url":null,"abstract":"Both Fas ligand (FasL) and tumor necrosis factor-alpha (TNF-alpha) are type II integral membrane proteins. Recently, we have reported that FasL is processed to a soluble form by an unknown metalloproteinase at the cell surface and some hydroxamate matrix metalloproteinase (MMP) inhibitors inhibit the processing similar to the case observed with TNF-1alpha. We studied the inhibitory effects of various hydroxamate MMP inhibitors on FasL and TNF-alpha processing in order to characterize the processing enzymes using human FasL cDNA transfectants and LPS-stimulated THP-1 cells. It turned out that (1) the P1' group of hydroxamates was very important for the selective inhibitory activity toward TNF-alpha and FasL processing, (2) P1' 3-phenylpropyl group was favorable for the inhibition of FasL processing, and (3) P1' isobutyl and isopropyl groups were favorable for that of TNF-alpha processing. These differences in sensitivity to inhibitors imply that (1) membrane-bound FasL and TNF-alpha might be processed by distinct metalloproteinases, (2) the S1' site of FasL processing enzyme differs from that of MMP-1 and MMP-9, but appears to be similar to that of MMP-3, and (3) the S1' site of TNF-alpha processing enzyme is smaller than that of FasL processing enzyme. These results would be helpful in designing a more selective inhibitor.","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 2","pages":"119-30"},"PeriodicalIF":0.0,"publicationDate":"1999-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21394943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Analysis of affinities of penicillins for a class C beta-lactamase by molecular dynamics simulations. 用分子动力学模拟分析青霉素对C类β -内酰胺酶的亲和力。

Drug design and discovery Pub Date : 1999-08-01 DOI: 10.1007/978-1-4615-4141-7_95

K. Tsuchida, N. Yamaotsu, S. Hirono

引用次数: 3

3D-pharmacophore analyses of aldose reductase inhibitory spiroquinazolinones. 醛糖还原酶抑制螺喹唑啉酮类药物的3d药效团分析。

Drug design and discovery Pub Date : 1999-08-01

K Nakao, M Asao, H Shirai, R Shimizu

引用次数: 0

Analysis of affinities of penicillins for a class C beta-lactamase by molecular dynamics simulations. 用分子动力学模拟分析青霉素对C类β -内酰胺酶的亲和力。

Drug design and discovery Pub Date : 1999-08-01

K Tsuchida, N Yamaotsu, S Hirono

{"title":"Analysis of affinities of penicillins for a class C beta-lactamase by molecular dynamics simulations.","authors":"K Tsuchida, N Yamaotsu, S Hirono","doi":"","DOIUrl":"","url":null,"abstract":"We present a calculation for the binding free energy difference between two complexes of the class C beta-lactamase from Enterobacter cloacae with foramidocillin (FOPC) and with piperacillin (PIPC). The calculation was carried out by means of the thermodynamic integration (TI) method implemented with molecular dynamics (MD). By use of the available crystal structure of the class C beta-lactamase from E. cloacae, the structures of the beta-lactamase-FOPC (FOPC complex) and beta-lactamase-PIPC (PIPC complex) complexes were built by molecular modeling and equilibrated with MD simulations. FOPC were gradually converted into PIPC in both the solution and the enzyme system by means of MD/TI methods during the MD simulation. The structure of the PIPC complex as derived by the MD/TI simulation was similar to that of the PIPC complex obtained from molecular modeling. The calculated difference in the free energy of binding (deltadeltaGbind) was -2.2 kcal/mol. This compares well with the experimental value of -1.5 kcal/mol. The results indicate that the binding affinity of FOPC is lower than that of PIPC because of the greater difficulty of desolvation for FOPC upon binding to the enzyme. This calculation suggests that the desolvation of the ligand, as well as its interaction with the beta-lactamase, is important in understanding the relative affinity of the ligands with beta-lactamase.","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 2","pages":"145-53"},"PeriodicalIF":0.0,"publicationDate":"1999-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21394945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A new class of diacidic nonpeptide angiotensin II receptor antagonists: candesartan cilexetil. 一类新的二酸非肽血管紧张素II受体拮抗剂:坎地沙坦西莱西酯。

Drug design and discovery Pub Date : 1999-08-01

T Naka, K Kubo, Y Inada, K Nishikawa

引用次数: 0