Abstract：
:A series of new peroxisome proliferator activated receptors (PPARs) chiral ligands have been designed following the accepted three-module structure comprising a polar head, linker, and hydrophobic tail. The majority of the ligands incorporate the oxazolidinone moiety as a novel polar head, and the nature of the hydrophobic tail has also been varied. Docking studies using the crystal structure of an agonist bound to the ligand binding domain of the PPARα receptor have been performed as a tool for their design. Suitable synthetic procedures have been developed, and compounds with different stereochemistries have been prepared. Evaluation of basal and ligand-induced activity proved that several compounds showed agonist activity at the PPARα receptor, thus validating the oxazolidinone template for PPAR activity. In addition, two compounds, 2 and 4, showed dual PPARα/PPARγ agonism and interesting food intake reduction in rats.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Fresno N,Macías-González M,Torres-Zaguirre A,Romero-Cuevas M,Sanz-Camacho P,Elguero J,Pavón FJ,Rodríguez de Fonseca F,Goya P,Pérez-Fernández Rdoi
10.1021/acs.jmedchem.5b00849subject
Has Abstractpub_date
2015-08-27 00:00:00pages
6639-52issue
16eissn
0022-2623issn
1520-4804journal_volume
58pub_type
杂志文章abstract：:Phthalocyanines (Pcs) are a class of photosensitizers (PSs) with a strong tendency to aggregate in aqueous environment, which has a negative influence on their photosensitizing ability in photodynamic therapy. Pcs with either peripheral or axial solketal substituents, that is, ZnPc(sol)8 and Si(sol)2Pc, respectively, ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm061136w
更新日期：2007-04-05 00:00:00
abstract：:3',5'-Diamino-3',5'-dideoxythymidine (7) was synthesized via a nine-step synthesis from thymidine in good overall yield. 3'-Amino-3'-deoxythymidine (8) and 5'-amino-5'-deoxythymidine (12) were prepared with a minor modification of the procedure reported by Horwitz and co-workers. Although the 5'-amino analogue 12 had ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：
更新日期：1978-01-01 00:00:00
abstract：:We have determined an X-ray crystal structure for the N-methyl iodide derivative of the nonsteroidal contraceptive centchroman. The pendant aromatic substituents on C-3 and C-4 of the chroman system are nearly perpendicular to the plane of the chroman system, an orientation expected in such a chroman, but perturbed to...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00031a020
更新日期：1994-03-04 00:00:00
abstract：:A series of 1-amino- and 1-mercapto-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyrans was synthesized and subsequently evaluated in three rodent test systems for CNS activity. The structure-activity data generated indicate that, in general, a change of the 1-hydroxy group to an amine results in a retention of pharmacological ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00211a004
更新日期：1977-01-01 00:00:00
abstract：:Taking advantage of a proposed hydrophobic region on 5-HT2 receptors previously identified by radioligand-binding studies utilizing various phenylisopropylamine derivatives, we prepared and evaluated several N1 - and/or C7-alkyl-substituted derivatives of alpha-methyltryptamine in order to improve its affinity and sel...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00172a016
更新日期：1990-10-01 00:00:00
abstract：:Three [5-t-BuPro(7)]oxytocin analogues were synthesized by substituting (2S,5R)-5-tert-butylproline for proline in oxytocin, [Mpa(1)]oxytocin, and [dPen(1)]oxytocin. Relative to oxytocin, [5-t-BuPro(7)]oxytocin and [Mpa(1),5-t-BuPro(7)]oxytocin exhibited strongly reduced binding affinity to the receptor; however, both...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990090m
更新日期：2000-04-20 00:00:00
abstract：:If no structural information about a particular target protein is available, methods of rational drug design try to superimpose putative ligands with a given reference, e.g., an endogenous ligand. The goal of such structural alignments is, on the one hand, to approximate the binding geometry and, on the other hand, to...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm981037l
更新日期：1998-11-05 00:00:00
abstract：:A group of compounds, structurally related to metoprolol, in which the aromatic nucleus is formally moved stepwise away from the ethanolamine side chain, has been studied as adrenergic agonists and antagonists. All the compounds were active on the adrenergic receptors and showed similar affinity for the receptor regar...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00136a014
更新日期：1981-04-01 00:00:00
abstract：:Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compound...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00193
更新日期：2019-05-23 00:00:00
abstract：:Previously, we reported the thiourea antagonists 2a and 2b as potent and high affinity TRPV1 antagonists. For further optimization of the lead compounds, a series of their amide and alpha-substituted amide surrogates were investigated and novel chiral N-(2-benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]p...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm701049p
更新日期：2008-01-10 00:00:00
abstract：:omega-Acryloyl anionic surfactants, whose polar heads are derived from amino acids, have been telomerized to prepare polyanions of a predetermined molecular weight. The main goal of this study was to verify whether the antiviral activity is influenced by the degree of polymerization of the polyanions. The oligomeric p...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960493b
更新日期：1997-01-31 00:00:00
abstract：:Factors influencing dose potency of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) analogues in L1210 assays have been investigated by multiple regression analysis. The dependent variable was D40, the dose to provide 40% life extension in L1210 tests. Independent variables examined were chromatographic Rm val...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00137a009
更新日期：1981-05-01 00:00:00
abstract：:The ghrelin receptor displays a high constitutive activity suggested to be involved in the regulation of appetite and food intake. Here, we have created peptides with small changes in the core binding motif -wFw- of the hexapeptide KwFwLL-NH(2) that can swap the peptide behavior from inverse agonism to agonism, indica...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300414b
更新日期：2012-09-13 00:00:00
abstract：:A series of 3-acylbenzamidine (amidino)hydrazones 7a-h, the corresponding (hetero)aromatic congeners 7i-p, and 3,3'-bis-amidino-biaryls 25a-e were synthesized. The hydrazones 7a-p were prepared by conversion of the corresponding acyl nitriles 1a,c-d,i,n-p to the imido esters 3a,c-d,i and the amidines 5a,c-d,h-i, follo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00053a007
更新日期：1993-01-08 00:00:00
abstract：:A novel cytochrome P450, CYP53A15, was identified in the pathogenic filamentous ascomycete Cochliobolus lunatus. The protein, classified into the CYP53 family, was capable of para hydroxylation of benzoate. Benzoate is a key intermediate in the metabolism of aromatic compounds in fungi and yet basically toxic to the o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800030e
更新日期：2008-06-26 00:00:00
abstract：:In an effort to identify selective ligands for the estrogen receptor subtype ERbeta, a series of aryl benzthiophenes was synthesized. In a radioligand binding assay and reporter gene assays in HeLa and SH-SY5Y cells, compounds were characterized as ERbeta-selective agonists. By targeting ERbeta in the brain, these com...
journal_title：Journal of medicinal chemistry
pub_type： 信件
doi：10.1021/jm015577l
更新日期：2002-03-28 00:00:00
abstract：:A molecular model of the alpha3beta2 nAChR lumen channel was constructed and hydrophobic clefts were observed near the receptor gate. Docking simulations indicated that ligand-nAChR complexes were formed by hydrophobic interactions with the cleft and hydrogen bond interactions. The equilibrium constants and associatio...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070784s
更新日期：2007-11-29 00:00:00
abstract：:Extensions and refinements of the receptor mapping method as originally developed by Crippen are presented. In a set of newly developed algorithms measures are taken to reduce the number of required energy parameters to a statistically acceptable degree. The most important measure is the incorporation of lipophilicity...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00152a017
更新日期：1986-02-01 00:00:00
abstract：:The optimization of a series of aminooxazoline xanthene inhibitors of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aβ lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501266w
更新日期：2014-12-11 00:00:00
abstract：:The academic setting provides an environment that may foster success in the discovery of certain types of small molecule tools while proving less suitable in others. For example, small molecule probes for poorly understood systems, those that exploit a specific resident expertise, and those whose commercial return is ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/jm400132d
更新日期：2013-09-26 00:00:00
abstract：:The enantiomers of the leukotriene D4 antagonist 3-[[[3-[2-(7-chloroquinolin-2-yl)-(E)-ethenyl]phenyl] [[3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]propionic acid (L-660,711)(MK-571) have been prepared, their absolute stereochemistry has been assigned as S for (+)-1 and R for (-)-1 by X-ray analysis of a synthetic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00172a025
更新日期：1990-10-01 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：:Since the identification of the dopamine D(4) receptor subtype and speculations about its possible involvement in schizophrenia, much work has been put into development of selective D(4) ligands. These selective ligands may be effective antipsychotics without extrapyramidal side effects. This work describes the synthe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm031111m
更新日期：2004-06-03 00:00:00
abstract：:A critical early event in the inflammatory cascade is the induced expression of cell adhesion molecules on the lumenal surface of vascular endothelial cells. These adhesion molecules include E-selectin, ICAM-1, and VCAM-1, which serve to recruit circulating leukocytes to the site of the inflammation. These adhesive in...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000452m
更新日期：2001-03-15 00:00:00
abstract：:The mechanism of action of a general class of mechanism-based inhibitors of serine proteases, including human neutrophil elastase (HNE), has been elucidated by determining the X-ray crystal structure of an enzyme-inhibitor complex. The captured intermediate indicates that processing of inhibitor by the enzyme generate...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm700966p
更新日期：2008-04-10 00:00:00
abstract：:A consideration of the detailed structural information available from X-ray crystallographic and NMR studies on complexes of dihydrofolate reductase with inhibitors has led to the design of trimethoprim analogues with improved binding properties. Computer graphic techniques have been used to predict which substituent ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00378a025
更新日期：1984-12-01 00:00:00
abstract：:Given the emergence of resistance observed for the current clinical-stage hepatitis C virus (HCV) NS3 protease inhibitors, there is a need for new inhibitors with a higher barrier to resistance. We recently reported our rational approach to the discovery of macrocyclic acylsulfonamides as HCV protease inhibitors addre...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400121t
更新日期：2014-03-13 00:00:00
abstract：:NF-κB-inducing kinase (NIK) is a protein kinase central to the noncanonical NF-κB pathway downstream from multiple TNF receptor family members, including BAFF, which has been associated with B cell survival and maturation, dendritic cell activation, secondary lymphoid organ development, and bone metabolism. We report ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00678
更新日期：2018-08-09 00:00:00
abstract：:The new pyrimidine derivatives of 2,3-O, O-dibenzyl-6-deoxy-L-ascorbic acid (8-10) were synthesized by condensation of uracil and its 5-fluoro- and 5-trifluoromethyl-substituted derivatives with 4-(5,6-epoxypropyl)-2, 3-O,O-dibenzyl-L-ascorbic acid (7), while pyrimidine derivatives of 4,5-didehydro-5,6-dideoxy-L-ascor...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0009540
更新日期：2000-12-14 00:00:00
abstract：:Structural modifications requiring novel synthetic chemistry were made to the morpholine acetal human neurokinin-1 (hNK-1) receptor antagonist 4, and this resulted in the discovery of 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-ox o-1 ,2,4-triazol-5-yl)methyl morpholine (17). This m...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980299k
更新日期：1998-11-05 00:00:00
