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 synthesis of a new series of 2,4-disubstituted morpholines and 2,4-disubstituted 1,4-oxazepanes with selectivity for the dopamine D(4) receptor. A 3D-QSAR analysis using the GRID/GOLPE methodology was performed with the purpose to get a better understanding of the relationship between chemical structure and biological activity. Inspection of the coefficient plots allowed us to identify that regions which are important for affinity are situated around the two benzene ring systems, a p-chlorobenzyl group, and the aliphatic amine belonging to the morpholine or 1,4-oxazepane system. In addition, the size of the morpholine or 1,4-oxazepane ring seems to be important for affinity.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Audouze K,Nielsen EØ,Peters Ddoi
10.1021/jm031111mkeywords:
subject
Has Abstractpub_date
2004-06-03 00:00:00pages
3089-104issue
12eissn
0022-2623issn
1520-4804journal_volume
47pub_type
杂志文章abstract：:A study of the structure-activity relationships (SAR) of 2f (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed, targeting the 5-position of the oxazole. Examination of a series of substituted benzene derivatives (12-14) revealed that the optimal position for substitution was the meta-positi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0611509
更新日期：2007-03-08 00:00:00
abstract：:A new computational method for the in situ generation of small molecules within the binding site of a protein is described. The method has been evaluated using two well-studied systems, dihydrofolate reductase and thymidylate synthase. The method has also been used to guide improvements to inhibitors of HIV-1 protease...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00003a010
更新日期：1995-02-03 00:00:00
abstract：:A novel series of pyridazinone-functionalized phenylalanine analogues was prepared and evaluated for inhibition of cellular adhesion mediated by alpha4beta1/VCAM-1 and alpha4beta7/MAdCAM-1 interactions. Concise syntheses were developed and applied for exploration of structure-activity relationships pertaining to the p...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060031q
更新日期：2006-06-01 00:00:00
abstract：:A series of pseudodipeptide amides are described that inhibit Ras protein farnesyltransferase (PFTase). These inhibitors are truncated versions of the C-terminal tetrapeptide (CAAX motif) of Ras that serves as the signal sequence for PFTase-catalyzed protein farnesylation. In contrast to CAAX peptidomimetics previousl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00020a010
更新日期：1995-09-29 00:00:00
abstract：:The bradykinin B1 receptor is rapidly induced upon tissue injury and inflammation, stimulating the production of inflammatory mediators resulting in plasma extravasation, leukocyte trafficking, edema, and pain. We have previously reported on sulfonamide and sulfone-based B1 antagonists containing a privileged bicyclic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200808v
更新日期：2011-10-27 00:00:00
abstract：:C5-unsubstituted-C6-aryl-1,4-dihydropyridines were prepared by a CAN-catalyzed multicomponent reaction from chalcones, β-dicarbonyl compounds, and ammonium acetate. These compounds were able to block Ca(2+) entry after a depolarizing stimulus and showed an improved Cav1.3/Cav1.2 selectivity in comparison with nifedipi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500263v
更新日期：2014-05-22 00:00:00
abstract：:Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncology. Here, we report on the syntheses and activity of novel inhibitors of the thioesterase domain of FAS. Using the structure of orlistat as a starting point, which contains a beta-lactone as the centr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800321h
更新日期：2008-09-11 00:00:00
abstract：:Carbonates containing an iodinated aromatic ring on one side of the carbonate linkage and an alkyl group on the other were prepared. The aromatic side consisted of p-iodophenyl, p-iodobenzyl, m-iodobenzyl, 3,5-diiodobenzyl, m-amino-2,4,6-triiodobenzyl, m-acetamido-2,4,6-triiodobenzyl, p-iodophenethyl, p-iodo-sec-phene...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00234a002
更新日期：1976-12-01 00:00:00
abstract：:A number of 2-oxoquinoline-1-alkanoic acids that contain the N-acylglycine fragment found in several known inhibitors of aldose reductase were synthesized and tested in the rat lens assay. All of the target compounds were prepared by alkylation of the appropriate 2-oxoquinoline intermediates with a halo ester, followe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00160a038
更新日期：1986-10-01 00:00:00
abstract：:We have synthesized a series of N-phenyl-N'-aralkyl and N-phenyl-N'-(1-phenylcycloalkyl)ureas as inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). This intracellular enzyme is thought to be responsible for the esterification of dietary cholesterol; hence inhibition of this enzyme could reduce diet-induced hyp...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00074a011
更新日期：1993-10-29 00:00:00
abstract：:Macrophage elastase [matrix metalloproteinase (MMP)-12] is the most upregulated MMP in abdominal aortic aneurysm (AAA) and, hence, MMP-12-targeted imaging may predict AAA progression and rupture risk. Here, we report the design, synthesis, and evaluation of three novel hydroxamate-based selective MMP-12 inhibitors (CG...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01514
更新日期：2020-12-10 00:00:00
abstract：:We previously reported the discovery of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1'-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bipiperidine N-oxide 1 (SCH 351125) as an orally bioavailable human CCR5 antagonist for the treatment of HIV-1 infection. Herein, we describe in detail the discovery of 1 from our i...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0200815
更新日期：2002-07-04 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：:Hydroxy-2-phenylindoles carrying substituted benzyl groups and similar substituents at the nitrogen were synthesized and tested for their ability to displace estradiol from its receptor. All of the derivatives tested exhibited high binding affinities for the calf uterine estrogen receptor, with RBA values ranging from...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00384a022
更新日期：1987-01-01 00:00:00
abstract：:A novel, potent, and orally bioavailable inhibitor of hepatitis C RNA replication targeting NS4B, compound 4t (PTC725), has been identified through chemical optimization of the 6-(indol-2-yl)pyridine-3-sulfonamide 2 to improve DMPK and safety properties. The focus of the SAR investigations has been to identify the opt...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm401621g
更新日期：2014-03-13 00:00:00
abstract：:In an effort to develop selective inhibitors of vesicular acetylcholine storage, we have synthesized a series of semirigid vesamicol receptor ligands based on the structure of 2-(4-phenylpiperidino)-cyclohexanol (vesamicol, AH5183, 1). In these compounds, the planes of the phenyl and piperidyl moieties of the parent l...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00042a010
更新日期：1994-08-05 00:00:00
abstract：:We have designed and synthesized 16 new olean- and urs-1-en-3-one triterpenoids with various modified rings C as potential antiinflammatory and cancer chemopreventive agents and evaluated their inhibitory activities against production of nitric oxide induced by interferon-gamma in mouse macrophages. This investigation...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0002230
更新日期：2000-11-02 00:00:00
abstract：:Tuberculosis (TB) is a major health problem worldwide. We herein report a new class of pyrimidine nucleosides as potent inhibitors of Mycobacterium tuberculosis (M. tuberculosis). Various 2'- or 3'-halogeno derivatives of pyrimidine nucleosides containing uracil, 5-fluorouracil, and thymine bases were synthesized and ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100165w
更新日期：2010-05-27 00:00:00
abstract：:Human G93A-superoxide dismutase-1 (G93AhSOD1) mutation causes amyotrophic lateral sclerosis (ALS) in rodents and humans. Recent observations indicate gain of interaction of G93AhSOD1 with cytosolic malate dehydrogenase (MDH1) and subsequent impairment in the malate aspartate shuttle which is vital to neurons. Using fl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900631m
更新日期：2009-09-10 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：:Emerging studies have shown that mitochondrial DNA (mtDNA) is a potential target for cancer therapy. Herein, six cyclometalated Ir(III) complexes Ir1-Ir6 containing a series of extended planar diimine ligands have been designed and assessed for their efficacy as anticancer agents. Ir1-Ir6 show much higher cytotoxicity...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01704
更新日期：2019-04-11 00:00:00
abstract：:A promising strategy for selecting synthetic targets is similarity-based searching of very large "virtual libraries", which comprise all structures accessible by linking two or three commercially available building blocks with combinatorial syntheses. To assess the general applicability of this strategy, leading struc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000003m
更新日期：2000-05-04 00:00:00
abstract：:A series of 8-phenylxanthine derivatives has been synthesized with oxyacetic acid on the para phenyl position to increase aqueous solubility and minimize nonspecific binding and iodinatable groups on the 1- or 3-position of the xanthine ring. The structure-activity relationship for binding of these compounds to A1 ade...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00399a010
更新日期：1988-04-01 00:00:00
abstract：:We recently described a novel series of CA(1)A(2)X peptidomimetics as farnesyl transferase inhibitors (FTIs). These compounds possess an N-(4-piperidinyl)benzamide scaffold mimicking A(1)A(2) residue. Extensive exploration of structure--activity relationships revealed that replacement of cysteine by substituted benzyl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030502y
更新日期：2004-12-30 00:00:00
abstract：:A series of tricyclic analogues of 9-oxo-9H-xanthene-4-acetic acid have been prepared and evaluated for their ability to cause hemorrhagic necrosis in subcutaneously implanted colon 38 tumors in mice, in an effort to extend the structure-activity relationships for this series. As was found previously with analogues of...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00106a003
更新日期：1991-02-01 00:00:00
abstract：:17β-HSD14 is a SDR enzyme able to oxidize estradiol and 5-androstenediol using NAD(+). We determined the crystal structure of this human enzyme as the holo form and as ternary complexes with estrone and with the first potent, nonsteroidal inhibitor. The structures reveal a conical, rather large and lipophilic binding ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00293
更新日期：2016-07-28 00:00:00
abstract：:Motivated by the pivotal role of CXCR4 as an HIV entry co-receptor, we herein report a de novo hit-to-lead effort on the identification of subnanomolar purine-based CXCR4 antagonists against HIV-1 infection. Compound 24, with an EC50 of 0.5 nM against HIV-1 entry into host cells and an IC50 of 16.4 nM for inhibition o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501772w
更新日期：2015-02-12 00:00:00
abstract：:The maximum achievable accuracy of in silico models depends on the quality of the experimental data. Consequently, experimental uncertainty defines a natural upper limit to the predictive performance possible. Models that yield errors smaller than the experimental uncertainty are necessarily overtrained. A reliable es...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300131x
更新日期：2012-06-14 00:00:00
abstract：:Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0504555
更新日期：2005-10-20 00:00:00
abstract：:The (E)- and (Z)-m-(trifluoromethyl)-alpha, beta-dimethylcinnamamides and some of their N-alkyl derivatives were prepared and pharmacologically tested as anticonvulsant agents in order to verify if a ring substituent, like the m-CF3 group, different from a halogen but possessing the same electronic effect could lead t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00137a010
更新日期：1981-05-01 00:00:00
