Abstract:
:Analogues of angiotensin II and III (ANG II and ANG III) in which the tyrosine and/or phenylalanine residues were substituted have been synthesized by the solid-phase method and purified by (carboxymethyl)cellulose chromatography and reversed-phase HPLC. The antagonist and agonist potencies of these peptides were determined in the rat isolated uterus assay. [Sar1,Tyr(Me)4]ANG II, [Tyr(Me)3]ANG III, [Sar1,D-Trp4]ANG II, [D-Trp3]ANG III, [Sar1,D-Trp8]ANG II, [D-Trp7]ANG III, [Sar1,Tyr(Me)4,Ile8]ANG II, [Tyr(Me)3,Ile7]ANG III, [Sar1,D-Trp4,Ile8]ANG II, [D-Trp3,Ile7]ANG III, [Sar1,Tyr(Me)4,D-Trp8]ANG II, and [Tyr(Me)3,D-Trp7]ANG III had antagonist activities (pA2) respectively of 8.1, less than 6, less than 6, less than 6, (7.7), (6.7), 7.2, less than 6, less than 6, less than 6, 7.1, and less than 6. The agonist activity of each peptide was less than 0.1% of that of ANG II. Analogues in which only the Phe residue was substituted were not readily reversible in the bioassay, whereas analogues in which only the Tyr residue or both the Tyr and Phe residues were substituted were reversible antagonists. Peptides that were twice substituted had lower antagonist activities than peptides having a single aromatic residue substitution. Substitution of the Tyr residue in ANG II, but not ANG III, provides a new route for the synthesis of potent and competitive angiotensin antagonists. Differences in the biological properties of ANG II and ANG III analogues substituted at the Tyr residue suggest different binding/conformation requirements for the two endogenous ligands at angiotensin receptors in smooth muscle.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Matsoukas JM,Goghari MH,Scanlon MN,Franklin KJ,Moore GJdoi
10.1021/jm00383a015subject
Has Abstractpub_date
1985-06-01 00:00:00pages
780-3issue
6eissn
0022-2623issn
1520-4804journal_volume
28pub_type
杂志文章abstract::Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this l...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm5013352
更新日期:2015-01-08 00:00:00
abstract::The leukotrienes, metabolites of arachidonic acid produced through the action of the enzyme 5-lipoxygenase, are important mediators of immediate hypersensitivity and inflammation. Among the variety of diseases in which the leukotrienes may play a symptomatic or causative role is the dermatological condition psoriasis,...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00165a005
更新日期:1990-03-01 00:00:00
abstract::A variety of nitroheterocyclic carbamate prodrugs of phenylenediamine mustard and 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-benz[e]indoline (amino-seco-CBI-TMI), covering a wide range of reduction potential, were prepared and evaluated for use in gene-directed enzyme prodrug ther...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm030308b
更新日期:2003-12-04 00:00:00
abstract::We disclose the first selective, nonpeptidic, small-molecule somatostatin receptor subtype 5 (SST5R) antagonists that were identified by a chemogenomics approach based on the analysis of the homology of amino acids defining the putative consensus drug binding site of SST5R. With this strategy, opioid, histamine, dopam...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm701143p
更新日期:2007-12-13 00:00:00
abstract::Reformatski condensation of benzyl 2-bromopropionate with 4-carbomethoxybenzaldehyde, followed by dehydration afforded benzyl 2-methyl-p-carbomethoxycinnamate (4a). Hydrogenation over a Pd catalyst gave the hydrocinnamic acid 5a. Conversion to the chloromethyl (6a) and azidomethyl ketone (7a) was followed by hydrogena...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00163a035
更新日期:1990-01-01 00:00:00
abstract::In this paper, a peptide substrate (Pep8) of TSSK1 is identified. Using Pep8 as a substrate, two homogeneous and efficient assays for TSSK1 inhibitors screening have been developed, including luminescent kinase assay and LC-MS-based high-throughput assay. Two classes of compounds were identified that are able to effic...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9002846
更新日期:2009-07-23 00:00:00
abstract::2-Aminopyridine-3,5-dicarbonitrile compounds were previously identified as mimetics of dominant-negative prion protein mutants and inhibit prion replication in cultured cells. Here, we report findings from a comprehensive structure-activity relationship study of the 6-aminopyridine-3,5-dicarbonitrile scaffold. We iden...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm061045z
更新日期:2007-01-11 00:00:00
abstract::The design and synthesis of potent and selective neurokinin NK-2 receptor agonists 12 (GR64349) and 31 are described, together with structure-activity relationships for related analogues. Compound 12 (EC50 = 3.7 nM at NK-2 receptors in the rat colon; selectivity > 1000- and > 300-fold with respect to NK-1 and NK-3 rec...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00100a027
更新日期:1992-10-30 00:00:00
abstract::(+)-Deoxoartelinic acid (13), a new hydrolytically stable, water-soluble, and potent non-acetal-type antimalarial drug candidate, was successfully prepared from artemisinic acid by using sulfur ylide and photooxygenative cyclization in seven steps. This compound showed superior in vitro antimalarial activity against t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm020244p
更新日期:2002-10-24 00:00:00
abstract::The synthesis and gastric antisecretory activities of the delta 4,5-cis, delta 4,5-trans, and 4,5-acetylenic analogues of 15-deoxy-16-hydroxy-16-methyl prostaglandin E1 methyl ester are described. The key step in the preparation of these compounds involved the stereospecific conjugate addition of a cuprate reagent to ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00360a002
更新日期:1983-06-01 00:00:00
abstract::A series of 8-(substituted phenyl) derivatives of theophylline and other 1,3-dialkylxanthines were evaluated for potency and selectivity as antagonists at A1- and A2-adenosine receptors in brain tissue. Theophylline has a similar potency (Ki = 14 microM) at both A1 and A2 receptors. 8-Phenyltheophylline is 25-35-fold ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00382a018
更新日期:1985-04-01 00:00:00
abstract::Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of E...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b00421
更新日期:2018-06-14 00:00:00
abstract::Recently we reported the synthesis of the first enantiomeric pair of irreversible opioid ligands [(3S,4R)-(-)- and (3R,4S)-(+)-cis-4, SUPERFIT] and specific interaction of the latter with the delta receptor. Here we report another enantiomeric pair of irreversible opioid ligands, (+)-trans- and (-)-trans-3-methylfenta...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00126a040
更新日期:1989-06-01 00:00:00
abstract::4,5-Diphenyl-2-oxazolenonanoic acid (18b) was synthesized and found to inhibit ADP-induced aggregation of human platelets with an IC50 of 2.5 microM. Acid 18b displaced [3H]iloprost from human platelet membranes in a concentration-dependent fashion, consistent with 18b inhibiting platelet function by acting as a prost...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00097a006
更新日期:1992-09-18 00:00:00
abstract::The Keap1 (Kelch-like ECH-associated protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) pathway is the major defending mechanism against oxidative stresses, and directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) has been an attractive strategy to target o...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c01116
更新日期:2020-10-08 00:00:00
abstract::A series of 3-(4-acylaminopiperazin-1-ylalkyl)indoles was synthesized and tested for antihypertensive activity. Compounds with no substituents in the indole portion of the molecule were generally most effective in lowering blood pressure in the spontaneous hypertensive rat model. Of these several analogues were very p...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00221a024
更新日期:1977-11-01 00:00:00
abstract::The increasing prevalence of diabetes has accelerated the search for new drugs derived from natural sources. To define the functional features of two such families of compounds, the flavonols and the ethyl caffeates, we have determined the high-resolution structures of representative inhibitors in complex with human p...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm301273u
更新日期:2012-11-26 00:00:00
abstract::Inhibitors of adenosine deaminase (ADA, EC 3.5.4.4) are potential therapeutic agents for the treatment of various health disorders. Several highly potent inhibitors were previously identified, yet they exhibit unacceptable toxicities. We performed a SAR study involving a series of C2 or C8 substituted purine-riboside ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm101286g
更新日期:2011-01-13 00:00:00
abstract::The protein kinase MKK7 is linked to neuronal development and the onset of cancer. The field, however, lacks high-quality functional probes that would allow for the dissection of its detailed functions. Against this background, we describe an effective covalent inhibitor of MKK7 based on the pyrazolopyrimidine scaffol...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b00102
更新日期:2019-03-14 00:00:00
abstract::6-Substituted 6-deoxy-L-galactose (L-fucose) derivatives were synthesized as potential antimetabolites of L-fucose. The cytotoxic effects of these compounds were evaluated on P388 leukemia cells in culture. The L-fucose analogues which showed the most potent growth inhibition were the sulfonyl ester, bromo, and iodo d...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00194a017
更新日期:1979-08-01 00:00:00
abstract::The iodinated analogue of 1-[2-(4-aminophenyl)ethyl]-4-[3-(trifluoromethyl)phenyl]piperazine (PAPP), IPAPP (4), and the corresponding azido compound azido-IPAPP (5) were synthesized. The corresponding no-carrier-added 125I (T1/2 = 60 days, 35-60 keV) labeled compounds were also prepared. High specific binding was obse...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00123a006
更新日期:1989-03-01 00:00:00
abstract::Three N-C8-bridged analogues 4-6 of the opiate etorphine (3) were synthesized and evaluated for opiate agonism and antagonism. In each case ring closure was effected by intramolecular N-alkylation with a suitably developed C8 side chain. Another key synthetic step was the selective monoprotection of diol 11, which all...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00394a016
更新日期:1987-11-01 00:00:00
abstract::To understand how chloroquine (CQ) enhances transgene expression in polycation-based, nonviral gene delivery systems, a number of CQ analogues with variations in the aliphatic amino side chain or in the aromatic ring are synthesized and investigated. Our studies indicate that the aliphatic amino moiety of CQ is essent...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm060736s
更新日期:2006-11-02 00:00:00
abstract::Proteins which bind methylated lysines ("readers" of the histone code) are important components in the epigenetic regulation of gene expression and can also modulate other proteins that contain methyl-lysine such as p53 and Rb. Recognition of methyl-lysine marks by MBT domains leads to compaction of chromatin and a re...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm200045v
更新日期:2011-04-14 00:00:00
abstract::The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC(50) = 6.1 ± 1.0 nM) from in-house screening. Detailed structure-activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallo...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm300334d
更新日期:2012-09-13 00:00:00
abstract::Spatial correspondence between apomorphine, a prototype dopaminergic (DA) drug, and ergoline and some of its (partial) analogues were derived by matching their molecular electrostatic potential (MEP) patterns surrounding the aromatic moieties with respect to the coincident aliphatic N atoms. The MEP patterns were calc...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00158a017
更新日期:1986-08-01 00:00:00
abstract::A series of substituted (E)-3-(4-oxo-4H-quinazolin-3-yl)-2-propenoic acids was prepared and evaluated in the rat passive cutaneous anaphylaxis (PCA) test for antiallergic activity. Alkoxy, alkylthio, and isopropyl substituents at the 6- or 8-positions provided highly potent compounds. Conversion to the Z isomer, reduc...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00357a018
更新日期:1983-03-01 00:00:00
abstract::Cell cycle experiments with our previously reported 4-biphenylaminoquinazoline (1-3) multityrosine kinase inhibitors revealed an activity profile resembling that of known tubulin polymerization inhibitors. Novel 4-biarylaminoquinazoline analogues of compound 2 were synthesized and evaluated as inhibitors of several ty...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm500034j
更新日期:2014-06-12 00:00:00
abstract::Design of small-molecule inhibitors (MDM2 inhibitors) to block the MDM2-p53 protein-protein interaction has been pursued as a new cancer therapeutic strategy. In recent years, potent, selective, and efficacious MDM2 inhibitors have been successfully obtained and seven such compounds have been advanced into early phase...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/jm501092z
更新日期:2015-02-12 00:00:00
abstract::A series of pepstatin analogues having structural variations in the P2', P1', and P2 positions have been synthesized and tested for inhibition of porcine pepsin. The standard peptide for this study was Iva-Sta-Val-Ala-Iaa. Structural variations in the P2' and P1' positions have relatively little effect on Ki; however,...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00360a022
更新日期:1983-06-01 00:00:00