Abstract：
:Prealbumin is a major thyroxine binding protein in blood that has been well studied crystallographically and has also been proposed as a model for the thyroxine nuclear receptor in tissue. The high-affinity T4 binding site in prealbumin gave a linear plot on Scatchard analysis. The interactions of selected polychlorinated biphenyls (PCBs) with prealbumin have been studied with use of computer graphics and predictions made regarding relative binding affinities for such structures. These modeling predictions were tested by using competitive binding experiments involving selected PCBs and hydroxylated derivatives as soluble structural probes. The results are in excellent agreement with the modeling predictions and demonstrated that these compounds can be highly effective (3-8 times better than thyroxine itself) competitive binding ligands for thyroxine specific binding sites in prealbumin. Laterally (3,3',5,5'-) substituted PCBs show the highest binding activity and further substitution on nonlateral (2,2',6,6'-) positions lowers binding activity. Lateral chlorine substitution was common to all PCBs studied that showed high binding affinities. The binding model may also suggest a preference for a linear and symmetrical molecular shape. These structural requirements for binding are substantially consistent with the structure-toxicity relationship for closely related compounds of environmental interest. These specific binding interactions are likely to modulate the distribution of certain PCBs and related compounds and alter hormone-protein interactions that are responsible for the maintenance of normal thyroid status. Since prealbumin is also a model for the putative thyroxine nuclear receptor in tissue, our hypothesis that high toxicity of certain halogenated aromatic hydrocarbons is at least in part due to their thyromimetic properties is further supported.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Rickenbacher U,McKinney JD,Oatley SJ,Blake CCdoi
10.1021/jm00155a010subject
Has Abstractpub_date
1986-05-01 00:00:00pages
641-8issue
5eissn
0022-2623issn
1520-4804journal_volume
29pub_type
杂志文章abstract：:Squalestatins without either the hydroxy group at C-4 or the carboxylic acid at C-3 or C-4 were prepared and evaluated for their ability to inhibit rat liver microsomal squalene synthase (SQS) in vitro. These modifications were well tolerated for compounds with the 4,6-dimethyloctenoate ester at C-6 (S1 series). Howev...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9504969
更新日期：1996-01-05 00:00:00
abstract：:This is a review of the macrolide and ketolide field focusing on differentiating the pharmacodynamics and especially the toxicology of the macrolides and ketolides. We emphasize the diversity in pharmacodynamics and toxicity of the macrolides and ketolides, resulting from even small structural changes, which makes it ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01159
更新日期：2020-06-25 00:00:00
abstract：:Undetected pan-assay interference compounds (PAINS) with false-positive activities in assays often propagate through medicinal chemistry programs and compromise their outcomes. Although a large number of PAINS have been classified, often on the basis of individual studies or chemical experience, little has been done s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00154
更新日期：2017-05-11 00:00:00
abstract：:A series of novel chiral 7-(1-, 3-, 4-, and 6-methyl-[(1R,4R)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-substituted naphthyridines has been prepared with the aim of obtaining good in vitro and in vivo antibacterial agents with a decrease of the pseudoallergic type reaction when compared to that observed with 7[(1R,4R)-2,5-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00093a024
更新日期：1992-07-24 00:00:00
abstract：:Calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated clinical efficacy in the treatment of acute migraine. Herein, we describe the design, synthesis, and preclinical characterization of a highly potent, oral CGRP receptor antagonist BMS-927711 (8). Compound 8 has good oral bioavailability in r...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm3013147
更新日期：2012-12-13 00:00:00
abstract：:GPR52 is an orphan G protein-coupled receptor (GPCR) that has been recently implicated as a potential drug target of Huntington's disease (HD), an incurable monogenic neurodegenerative disorder. In this research, we found that striatal knockdown of GPR52 reduces mHTT levels in adult HdhQ140 mice, validating GPR52 as a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01133
更新日期：2021-01-28 00:00:00
abstract：:Quantitative structure-activity studies were carried out on a series of N-isopropylaryl hydrazides which inhibits monoamine oxidase (MAO). The inhibitory potencies of these compounds of MAO were found to correlate with the electron-withdrawing capacity of the aryl ring substituents as estimated by both empirical Hamme...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00227a005
更新日期：1976-05-01 00:00:00
abstract：:Thrombin, a serine protease, plays a central role in the initiation and propagation of thrombotic events. An extensive search for new thrombin inhibitors was performed, using an unconventional approach. Screening of small basic molecules for binding in the recognition pocket of thrombin led to the discovery of (aminoi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00049a008
更新日期：1994-11-11 00:00:00
abstract：:The novel phenylalanine analogues 4'-[N-((4'-phenyl)phenethyl)carboxamido]phenylalanine (Bcp) and 2',6'-dimethyl-4'-[N-((4'-phenyl)phenethyl)carboxamido]phenylalanine (Dbcp) were substituted for Tyr(1) in the delta opioid antagonist TIPP (H-Tyr-Tic-Phe-Phe-OH; Tic = tetrahydroisoquinoline-3-carboxylic acid). Unexpecte...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9004913
更新日期：2009-11-12 00:00:00
abstract：:The inhibition of chicken liver dihydrofolate reductase by a series of substituted benzylpyrimidines has been investigated. From the inhibition constants a quantitative structure-activity relationship has been formulated. This mathematical model is compared with molecular graphics models constructed from the X-ray cry...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00155a006
更新日期：1986-05-01 00:00:00
abstract：:A series of 5-nitrofuran-2- and 3-carboxamides bearing alkylating side-chains has been synthesized and tested for their ability to radiosensitize selectively hypoxic Chinese hamster cells (V79) to the lethal effects of ionizing radiation and also for their ability to act directly and selectively as cytotoxic drugs on ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00171a027
更新日期：1990-09-01 00:00:00
abstract：:Three series of H(4) receptor ligands, derived from indoly-2-yl-(4-methyl-piperazin-1-yl)-methanones, have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. In all cases, substitution of small lipophilic groups in the 4...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0502081
更新日期：2005-12-29 00:00:00
abstract：:Interesting analgesic activity approaching that of meperidine and codeine was observed in standard animal models for 8-chloro-3,4-dihydro-5-methoxy-2-pyrrolidinomethylnaphthalene (compound 7). This compound was orally effective and its analgesic activity was not reversed by the opiate antagonist, naloxone. A limited n...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00201a004
更新日期：1978-03-01 00:00:00
abstract：:A variety of 1,2,4,5,7-pentoxocane and 1,2,4,5-tetroxane derivatives were prepared as potential peroxide antimalarial agents. In both series of cyclic peroxides, the steric and electronic effects of the substituents attached to the peroxide ring exert a remarkable influence on the antimalarial activity. For some cycli...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990014j
更新日期：1999-07-15 00:00:00
abstract：:Privileged structures are ligand substructures that are widely used to generate high-affinity ligands for more than one type of receptor. To explain this, we surmised that there must be some common feature in the target proteins. For a set of class A GPCRs, we found a good correlation between conservation patterns of ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0309452
更新日期：2004-02-12 00:00:00
abstract：:The dynorphin (Dyn) A analogue zyklophin ([N-benzyl-Tyr(1)-cyclo(d-Asp(5),Dap(8))]dynorphin A(1-11)NH2) is a kappa opioid receptor (KOR)-selective antagonist in vitro, is active in vivo, and antagonizes KOR in the CNS after systemic administration. Hence, we synthesized zyklophin analogues to explore the structure-act...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501827k
更新日期：2015-11-25 00:00:00
abstract：:New analogs of cyclic amino acid-conjugated bile acids were synthesized, and their physicochemical and biological properties were compared with those of natural analogs. Ursodeoxycholic acid was amidated with D-proline, L-proline, 4-hydroxy-L-proline, and 4-methoxy-L-proline. Hyocholic and hyodeoxycholic acids were am...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9508503
更新日期：1996-05-24 00:00:00
abstract：:This paper describes the synthesis and biological evaluation of a new class of peptidomimetic falcipain-2 inhibitors based on a 1,4-benzodiazepine scaffold combined with various alpha,beta-unsaturated electrophilic functions such as vinyl-ketone, -amide, -ester, and -nitrile. The profile of reactivity of this class of...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900047j
更新日期：2009-04-09 00:00:00
abstract：:The mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) is currently in clinical trial as an anticancer drug. A series of acridine-substituted analogues were prepared, using a new synthetic route to substituted acridine-4-carboxylic acids (conversion of substituted diphenylamine ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970004n
更新日期：1997-06-06 00:00:00
abstract：:Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippoca...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm5011012
更新日期：2014-11-13 00:00:00
abstract：:Several potentially irreversible ligands (i.e., wash-resistant binding inhibitors) for the cocaine receptor site on the dopamine transporter, derived from (-)-cocaine or 3 beta-phenyltropan-2 beta-carboxylic acid methyl ester (WIN 35,065-2), were prepared and shown to produce wash-resistant inhibition of [3H]-3 beta-(...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00088a017
更新日期：1992-05-15 00:00:00
abstract：:With the emergence of oseltamivir-resistant influenza viruses and in view of a highly pathogenic flu pandemic, it is important to develop new anti-influenza agents. Here, the development of neuraminidase (NA) inhibitors that were designed to overcome resistance mechanisms along with unfavorable pharmacokinetic (PK) pr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm401492x
更新日期：2014-02-13 00:00:00
abstract：:Here, we report the synthesis of a designed multi-pharmacophore ligand derived from the linkage of a delta selective peptide antagonist (Dmt-Tic) and a mu/kappa morphinan agonist butorphan (MCL 101) through a two methylene spacer. The new compound MCL 450 maintains the same characteristics as those the two reference c...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0605785
更新日期：2006-09-07 00:00:00
abstract：:A series of pyridines and other six-membered ring heterocycles connected to a biphenyltetrazole with a -CH2-NR'-link (1) were discovered to be potent angiotensin II antagonists. In the pyrimidine carboxylic acid series (W = CR, X = N, Y = CH, Z = COOH), compounds with an alkyl group (R') on the exocyclic nitrogen were...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00070a012
更新日期：1993-09-03 00:00:00
abstract：:Malaria represents a significant health issue, and novel and effective drugs are needed to address parasite resistance that has emerged to the current drug arsenal. Antimalarial drug discovery has historically benefited from a whole-cell (phenotypic) screening approach to identify lead molecules. This approach has bee...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/jm400314m
更新日期：2013-10-24 00:00:00
abstract：:Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibito...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01869
更新日期：2018-04-26 00:00:00
abstract：:The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, res...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00389
更新日期：2016-06-23 00:00:00
abstract：:A series of new HIV-1 protease inhibitors with the hydroxyethylamine core and different phenyloxazolidinone P2 ligands were designed and synthesized. Variation of phenyl substitutions at the P2 and P2' moieties significantly affected the binding affinity and antiviral potency of the inhibitors. In general, compounds w...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm1008743
更新日期：2010-11-11 00:00:00
abstract：:G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs....
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,随机对照试验
doi：10.1021/jm2010964
更新日期：2012-04-26 00:00:00
abstract：:Thirty-five analogues of Phe-Leu-Glu-Glu-Leu, the pentapeptide sequence 5-9 of bovine prothrombin precursor, were synthesized and assayed as potential substrates or inhibitors of rat liver vitamin K dependent carboxylase. Carboxylation of substrate was determined by measuring the incorporation of carbon-24 labeled bic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00138a013
更新日期：1981-06-01 00:00:00
