Abstract:
:Peptide mimetics of the RGDF sequence in which Arg-Gly has been replaced with 5-(4-amidinophenyl)pentanoyl mimetic has led to a 1000-fold increase in inhibitory potency over the natural RGDF ligand. The guanidine residue of the arginine may be involved in a reinforced ionic interaction with a carboxylate of the receptor which could explain the dramatic increase in potency upon replacement with benzamidine. This hypothesis is supported by the observation of low inhibitory potency of the corresponding benzylamine (18) and no activity with the corresponding imidazoline derivative (19); plus, ab initio calculations on the respective complexes suggest that the benzamidine-carboxylate is more favorable than the guanidine-carboxylate interaction. The ED50 for the inhibition of ex vivo collagen induced platelet aggregation in the dog for SC-52012 (1) was 0.32 microgram/kg/min by iv infusion with a pharmacodynamic half-life for recovery of approximately 40 min.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Zablocki JA,Miyano M,Garland RB,Pireh D,Schretzman L,Rao SN,Lindmark RJ,Panzer-Knodle SG,Nicholson NS,Taite BBdoi
10.1021/jm00065a003subject
Has Abstract,Author List Incompletepub_date
1993-06-25 00:00:00pages
1811-9issue
13eissn
0022-2623issn
1520-4804journal_volume
36pub_type
杂志文章abstract::New chemotherapeutics are urgently needed to combat malaria. We previously reported on a novel series of antimalarial, ethylenediamine-based inhibitors of protein farnesyltransferase (PFT). In the current study, we designed and synthesized a series of second generation inhibitors, wherein the core ethylenediamine scaf...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm800113p
更新日期:2008-09-11 00:00:00
abstract::A series of 2,2-diarylethylamine derivatives has been examined for potential antidepressant activity in the tetrabenazine (TBZ) test. Diethanolamine 4 (McN-4187) was one of the more potent compounds despite its polar alcohol functionalities [ED50 values of 15 mg/kg (exploratory activity) and 1.5 mg/kg (ptosis)]. Struc...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00374a022
更新日期:1984-08-01 00:00:00
abstract::Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. Genetic knockdown of G9a inhibits cancer cell growth, and the dimethylation of p53 K373 results in the inactivation of p53. Initial SAR exploration of the ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm100478y
更新日期:2010-08-12 00:00:00
abstract::The synthesis, biological activity, and molecular modeling studies of C-ring-modified camptothecins are reported. A general synthetic protocol, based on "C-5 camptothecin (C-5-CPT) enolate chemistry", allows one to obtain various C5-substituted analogues. All new compounds, obtained as 1:1 epimeric mixtures, were test...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm801153y
更新日期:2009-02-26 00:00:00
abstract::To determine if the conjugation of a small receptor ligand to a peptidic carrier to potentially facilitate transport across the blood-brain barrier (BBB) by "molecular Trojan horse" transcytosis is feasible, we synthesized several transport peptide-fallypride fusion molecules as model systems and determined their bind...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm5004123
更新日期:2014-05-22 00:00:00
abstract::The proto-oncogenes NTRK1/2/3 encode the tropomyosin receptor kinases TrkA/B/C which play pivotal roles in neurobiology and cancer. We describe herein the discovery of [11C]-(R)-3 ([11C]-(R)-IPMICF16), a first-in-class positron emission tomography (PET) TrkB/C-targeting radiolabeled kinase inhibitor lead. Relying on e...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b00396
更新日期:2017-08-24 00:00:00
abstract::By applying a novel cell- and caspase-based HTS assay, 2-amino-3-cyano-7-(dimethylamino)-4-(3-methoxy-4,5-methylenedioxyphenyl)-4H-chromene (1a) has been identified as a potent apoptosis inducer. Compound 1a was found to induce nuclear fragmentation and PARP cleavage, as well as to arrest cells at the G(2)/M stage and...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049640t
更新日期:2004-12-02 00:00:00
abstract::Fragment-based drug discovery has become a powerful method for the generation of drug leads against therapeutic targets. Beyond the identification of novel and effective starting points for drug design, fragments have emerged as reliable tools for assessing protein druggability and identifying protein hot spots. Here,...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm201439b
更新日期:2012-02-09 00:00:00
abstract::The antibacterial properties of glycopeptide antibiotics are based on their interaction with the d-Ala-d-Ala containing pentapeptide of bacterial peptidoglycan. The hydrophobic amides of vancomycin (1), teicoplanin (2), teicoplanin aglycon (3), and eremomycin (4) were compared with similar amides of minimally or low a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm020320o
更新日期:2003-03-27 00:00:00
abstract::New 2-[2'-(dimethylamino)ethyl]-3H-dibenz[de,h]isoquinoline-1,3-diones with substituents at the 6- and 7-positions were prepared. Nucleophilic aromatic displacement was a key reaction in the syntheses. Ten of the new compounds were more potent than the unsubstituted compound, azonafide, in a panel of tumor cells inclu...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm950742g
更新日期:1996-04-12 00:00:00
abstract::In an effort to explore structural features affecting receptor recognition in a series of conformationally restricted tetrapeptides related to the cyclic, delta opioid receptor-selective analogue, [formula: see text] electronic, lipophilic, and steric effects at the Phe3 residue were assessed by substitution at differ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00087a006
更新日期:1992-05-01 00:00:00
abstract::The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and pot...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm501185j
更新日期:2015-02-26 00:00:00
abstract::Selenosemicarbazones show marked antitumor activity. However, their mechanism of action remains unknown. We examined the medicinal chemistry of the selenosemicarbazone, 2-acetylpyridine 4,4-dimethyl-3-selenosemicarbazone (Ap44mSe), and its iron and copper complexes to elucidate its mechanisms of action. Ap44mSe demons...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b01399
更新日期:2016-01-14 00:00:00
abstract::Cancer cell targeting peptides have emerged as a highly efficient approach for selective delivery of chemotherapeutics and diagnostics to different cancer cells. However, the use of α-peptides in pharmaceutical applications is hindered by their enzymatic degradation and low bioavailability. Starting with a 10-mer α-pe...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm200750x
更新日期:2011-11-10 00:00:00
abstract::An approach to the development of new anticandidal drugs is described that employs peptides as carriers of toxic agents into cells. 5-Flurorcytosine (5-FC) was chosen as a toxic agent with which to prepare 5-FC-peptide conjugates as models to test the carrier proposal. Model compounds were synthesized and then tested ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00195a019
更新日期:1979-09-01 00:00:00
abstract::Using a combination of in silico and experimental approaches, we present evidence that the G-quadruplex (G4) motif (an alternative higher-order DNA conformation) has regulatory potential. Genome-wide analyses of 99980 human, chimpanzee, mouse, and rat promoters showed enrichment of sequence with potential to adopt G4 ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm800448a
更新日期:2008-09-25 00:00:00
abstract::Probucol (1) and probucol analogues with the substitutions at the disulfide-linked carbon (2, 3) and an additional substitution at a tert-butyl of each phenolic ring (4) were tested for their ability to lower total serum cholesterol and prevent aortic atherosclerosis in modified Watanabe heritable hyperlipidemic (WHHL...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00105a046
更新日期:1991-01-01 00:00:00
abstract::We describe herein the design, synthesis, biological evaluation, and structure-activity relationship (SAR) studies of an innovative class of antimalarial agents based on a polyaromatic pharmacophore structurally related to clotrimazole and easy to synthesize by low-cost synthetic procedures. SAR studies delineated a n...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm701247k
更新日期:2008-03-13 00:00:00
abstract::The natural retinoid 9-cis-retinoic acid is an activating ligand for both the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are members of the retinoid/thyroid hormone/steroid hormone family of nuclear receptor proteins that activate gene transcription through specific response elements. Th...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00017a021
更新日期:1995-08-18 00:00:00
abstract::The diester 2a obtained from 1,1'-ferrocenedicarboxylic acid and the highly and indiscriminately cytotoxic fungal metabolite illudin M (1) displayed antiproliferative activity at submicromolar IC(50) (72 h) values against a panel of eight cancer cell lines. Compound 2a was about 40 times less toxic than 1 to nonmalign...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm200359n
更新日期:2011-09-22 00:00:00
abstract::Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of RORγt is conceptually new, unique for this specific nuclear receptor, and offers advantages over traditional orthosteric inhibition. Here, we report a highly...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b01372
更新日期:2020-01-09 00:00:00
abstract::Establishing quantitative relationships between molecular structure and broad biological effects has been a long-standing goal in drug discovery. Evaluation of the capacity of molecules to modulate protein functions is a prerequisite for understanding the relationship between molecular structure and in vivo biological...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050494g
更新日期:2005-11-03 00:00:00
abstract::Reverse hydroxamate-based inhibitors of IspC, a key enzyme of the non-mevalonate pathway of isoprenoid biosynthesis and a validated antimalarial target, were synthesized and biologically evaluated. The binding mode of one derivative in complex with EcIspC and a divalent metal ion was clarified by X-ray analysis. Pilot...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm200694q
更新日期:2011-10-13 00:00:00
abstract::Fragment based drug discovery (FBDD) is a widely used tool for discovering novel therapeutics. NMR is a powerful means for implementing FBDD, and several approaches have been proposed utilizing (1)H-(15)N heteronuclear single quantum coherence (HSQC) as well as one-dimensional (1)H and (19)F NMR to screen compound mix...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm201441k
更新日期:2012-01-26 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::The enantiomers of reduced haloperidol (3a), azaperol (3b), and the related compound BMY-14802 (3c) were prepared in high optical purity. The affinity of these compounds for dopamine D2 and D3 receptors, and sigma S1 and S2 sites was determined in vitro. Both enantiomers of 3a display greatly decreased affinity for D2...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00076a022
更新日期:1993-11-26 00:00:00
abstract::The use of deuteration in medicinal chemistry has exploded in the past years, and the FDA has recently approved the first deuterium-labeled drug. Precision deuteration goes beyond the pure and simple amelioration of the pharmacokinetic parameters of a drug and might provide an opportunity when facing problems in terms...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.8b01808
更新日期:2019-06-13 00:00:00
abstract::Pan assay interference compounds (PAINS) have become a paradigm for compound classes that might cause artifacts in biological assays. PAINS-defining substructures are typically contained in larger compounds. We have systematically examined X-ray structures of protein-ligand complexes for compounds containing PAINS mot...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b01780
更新日期:2018-02-08 00:00:00
abstract::It is now accepted that (-)-cocaine binds to specific recognition sites associated with monoamine transporters in the mammalian brain. In this study, several analogs of 3 beta-phenyltropane-2 beta-carboxylic acid methyl ester were prepared and their potency for inhibiting the binding of [3H]-3 beta-(4-fluorophenyl)tro...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00059a010
更新日期:1993-04-02 00:00:00
abstract::The hPepT1-mediated transport properties of a series of 11 synthesized beta- and gamma-peptides have been studied in Caco-2 cells. The results show that several of the compounds interact with the peptide transporter, but only two beta-dipeptides act as substrates and are transported across the cell monolayers. These t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm070148u
更新日期:2007-10-18 00:00:00