Abstract：
:Desformylflustrabromine (dFBr; 1), perhaps the first selective positive allosteric modulator of α4β2 neuronal nicotinic acetylcholine (nACh) receptors, was deconstructed to determine which structural features contribute to its actions on receptors expressed in Xenopus ooycytes using two-electrode voltage clamp techniques. Although the intact structure of 1 was found to be optimal, several deconstructed analogs retained activity. Neither the 6-bromo substituent nor the entire 2-position chain is required for activity. In particular, reduction of the olefinic side chain of 1, as seen with 6, not only resulted in retention of activity/potency but in enhanced selectivity for α4β2 versus α7 nACh receptors. Pharmacophoric features for the allosteric modulation of α4β2 nACh receptors by 1 were identified.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
German N,Kim JS,Jain A,Dukat M,Pandya A,Ma Y,Weltzin M,Schulte MK,Glennon RAdoi
10.1021/jm200834xsubject
Has Abstractpub_date
2011-10-27 00:00:00pages
7259-67issue
20eissn
0022-2623issn
1520-4804journal_volume
54pub_type
杂志文章abstract：:A series of next in class small-molecule hepatitis C virus (HCV) NS5A inhibitors with picomolar potency containing 2-pyrrolidin-2-yl-5-{4-[4-(2-pyrrolidin-2-yl-1H-imidazol-5-yl)buta-1,3-diynyl]phenyl}-1H-imidazole cores was designed based on the SAR studies available for the reported NS5A inhibitors. Compound 13a (AV4...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500951r
更新日期：2014-09-25 00:00:00
abstract：:Prostate-specific membrane antigen (PSMA) is an excellent biomarker for the early diagnosis of prostate cancer progression and metastasis. The most promising PSMA-targeted agents in the clinical phase are based on the Lys-urea-Glu motif, in which Lys and Glu are α-(l)-amino acids. In this study, we aimed to determine ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b02022
更新日期：2020-03-26 00:00:00
abstract：:The synthesis of new meridianin derivatives is described. The indolic ring system was substituted at the C-4 to C-7 positions either by a bromine atom or by nitro or amino groups. Additionally, an iodine atom or various aryl groups were introduced at the C-5 position of the 2-aminopyrimidine ring. These compounds as w...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200464w
更新日期：2011-07-14 00:00:00
abstract：:When cephalosporins exert their biological activity by reacting with bacterial enzymes, opening of the beta-lactam ring can lead to expulsion of the 3'-substituent. A series of cephalosporins was prepared in which antibacterial quinolones were linked to the 3'-position through a quaternary nitrogen. Like the 3'-ester-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00106a031
更新日期：1991-02-01 00:00:00
abstract：:We previously reported that (+/-)-6-(4-(benzylamino)-7-quinazolinyl)-4,5- dihydro-5-methyl-3(2H)-pyridazinone (+/-)-1, KF15232) showed potent cardiotonic activity with a strong myofibrillar Ca(2+)-sensitizing effect. As an extension of our work, we attempted to synthesize optically active 1. (+/-)-4-(4-(Benzylamino)-7...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950197j
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abstract：:Various 2',3'-dideoxy-L-cytidine,2',3'-dideoxy-L-uridine, and 3'-deoxy-L-thymidine analogues have been synthesized and evaluated in vitro as potential anti-HIV and anti-HBV agents. Coupling of 1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-L-ribofuranose (1) with silylated derivatives of 5-fluorocytosine, cytosi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00032a013
更新日期：1994-03-18 00:00:00
abstract：:Sepsis is characterized by a systemic inflammatory response syndrome. Derivatives of indole have been reported to exhibit diverse biological activities. This study reports on the design and synthesis of a new series of indole-2-carboxamide derivatives, which are screened for their anti-inflammatory activities in RAW 2...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b02006
更新日期：2016-05-26 00:00:00
abstract：:Screening in mixtures is a common approach for increasing the efficiency of high-throughput screening. Here we investigate how the "compound load" of mixtures influences promiscuous aggregate-based inhibition. We screened 764 molecules individually and in mixtures of 10 at 5 miccroM each, comparing the observed inhibi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060029z
更新日期：2006-04-06 00:00:00
abstract：:Two analogues, 6-(2-aminopropyl)-5-methoxy-2,3-dihydrobenzofuran and 6-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran, of the hallucinogenic agent 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) were synthesized and tested in the two-lever drug discrimination paradigm. In rats trained to discriminate s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00152a022
更新日期：1986-02-01 00:00:00
abstract：:The 3C-like proteinase (3CL(pro)) of severe acute respiratory syndrome (SARS) coronavirus is a key target for structure-based drug design against this viral infection. The enzyme recognizes peptide substrates with a glutamine residue at the P1 site. A series of keto-glutamine analogues with a phthalhydrazido group at ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0494873
更新日期：2004-12-02 00:00:00
abstract：:Fragment-based docking was used to select a conformation for virtual screening from a molecular dynamics trajectory of the West Nile virus nonstructural 3 protease. This conformation was chosen from an ensemble of 100 molecular dynamics snapshots because it optimally accommodates benzene, the most common ring in known...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900448m
更新日期：2009-08-13 00:00:00
abstract：:A series of regioisomeric substituted 6-O-benzyl ethers of 6 beta-naltrexol (12) in which isothiocyanate groups were attached directly to or one carbon removed from the aromatic ring of the benzyl group were prepared. These agents were prepared to obtain electrophilic opioid ligands potentially useful in the character...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00003a020
更新日期：1995-02-03 00:00:00
abstract：:A novel and highly efficient flexible docking approach is presented where the conformations (internal degrees of freedom) and orientations (external degrees of freedom) of the ligands are successively considered. This hybrid method takes advantage of the synergistic effects of structure-based and ligand-based drug des...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0311386
更新日期：2004-08-12 00:00:00
abstract：:The design, synthesis, and biological evaluation of a new class of inhibitors of thymidylate synthase (TS) is described. The molecular design was carried out by a repetitive crystallographic analysis of protein-ligand structures. At the onset of this project, we focused on the folate cofactor binding site of a high-re...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00058a010
更新日期：1993-03-19 00:00:00
abstract：:Development of orally available phosphodiesterase 4 (PDE4) inhibitors as anti-inflammatory drugs has been going on for decades. However, only roflumilast has received FDA approval. One key challenge has been the low therapeutic window observed in the clinic for PDE4 inhibitors, primarily due to PDE4 mediated side effe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/jm500378a
更新日期：2014-07-24 00:00:00
abstract：:In our continuing study of triterpene derivatives as potent anti-HIV agents, different C-3 conformationally restricted betulinic acid (BA, 1) derivatives were designed and synthesized in order to explore the conformational space of the C-3 pharmacophore. 3-O-Monomethylsuccinyl-betulinic acid (MSB) analogues were also ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm901782m
更新日期：2010-04-22 00:00:00
abstract：:Progesterone receptors (PRs) are present in many breast tumors, and their levels are increased by certain endocrine therapies. We describe the synthesis and PR binding affinities of a series of bromine- and iodine-substituted 16alpha,17alpha-dioxolane progestins, some of which, when appropriately radiolabeled, are pot...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060348q
更新日期：2006-07-27 00:00:00
abstract：:Various semicarbazones derived from aryl aldehydes, phenylalkyl aldehydes, and phenylalkyl ketones as well as some related compounds were evaluated for anticonvulsant activity. Most of the compounds displayed anticonvulsant activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00068a001
更新日期：1993-08-06 00:00:00
abstract：:A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD(+)-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm8012954
更新日期：2009-03-12 00:00:00
abstract：:The intense intrinsic fluorescence emissions from several clinically relevant camptothecin drugs have been exploited in order to study the structural basis of drug binding to human serum albumin. Both HPLC and time-resolved fluorescence spectroscopic methodologies were employed to characterize the associations of camp...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00027a005
更新日期：1994-01-07 00:00:00
abstract：:To study the influence of substitution of CN for C identical to CH in the anti-herpes virus nucleoside 5-(propynyloxy)-2'-deoxyuridine (1), 5-[(cyanomethylene)oxy]-2'-deoxyuridine (2) was prepared. When the potassium salt of 5-hydroxy-2'-deoxyuridine was reacted with iodoacetonitrile in dry DMF, the bisalkylated produ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00136a007
更新日期：1981-04-01 00:00:00
abstract：:The structure-based design, synthesis, and biological activity of a novel indazole-containing inhibitor series for S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described. Use of 5-aminoindazole as the core scaffold provided a structure-guided series of low nanomolar inhibitors with broad-spec...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0302039
更新日期：2003-12-18 00:00:00
abstract：:The three dimers 3, 4, and 5 of mitomycin C (MC), a natural antibiotic and cancer chemotherapeutic agent, were synthesized in which two MC molecules were linked with -(CH(2))(4)-, -(CH(2))(12)-, and -(CH(2))(3)N(CH(3))(CH(2))(3)- tethers, respectively. The dimeric mitomycins were designed to react as polyfunctional DN...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049863j
更新日期：2004-06-03 00:00:00
abstract：:Accumulation of beta-amyloid aggregates (Abeta) in the brain is linked to the pathogenesis of Alzheimer's disease (AD). We report a novel approach for producing 1,4-diphenyltriazoles as probes for targeting Abeta aggregates in the brain. The imaging probes, a series of substituted tricyclic 1,4-diphenyltriazoles showi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070467l
更新日期：2007-07-12 00:00:00
abstract：:Neutrophil serine proteases, proteinase 3 (PR3) and human neutrophil elastase (HNE), are considered as targets for chronic inflammatory diseases. Despite sharing high sequence similarity, the two enzymes have different substrate specificities and functions. While a plethora of HNE inhibitors exist, PR3 specific inhibi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500782s
更新日期：2014-11-26 00:00:00
abstract：:Inhibition of the cell cycle kinase, cyclin-dependent kinase-4 (Cdk4), is expected to provide an effective method for the treatment of proliferative diseases such as cancer. The pyrido[2,3-d]pyrimidin-7-one template has been identified previously as a privileged structure for the inhibition of ATP-dependent kinases, a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049355+
更新日期：2005-04-07 00:00:00
abstract：:CXCL12 binds to CXCR4, promoting both chemotaxis of lymphocytes and metastasis of cancer cells. We previously identified small molecule ligands that bind CXCL12 and block CXCR4-mediated chemotaxis. We now report a 1.9 Å resolution X-ray structure of CXCL12 bound by such a molecule at a site normally bound by sY21 of C...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501194p
更新日期：2014-11-26 00:00:00
abstract：:Novel bisbenzimidazole inhibitors of bacterial type IA topoisomerase are of interest for the development of new antibacterial agents that are impacted by target-mediated cross resistance with fluoroquinolones. The present study demonstrates the successful synthesis and evaluation of bisbenzimidazole analogues as Esche...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm5003028
更新日期：2014-06-26 00:00:00
abstract：:In our search for potent and receptor-selective agonists and antagonists, we report here the results of D-amino acid substitution at each position of the short peptide gamma-melanocyte-stimulating hormone (gamma-MSH). The native gamma-MSH shows weak binding at all three receptors (i.e., the human MC3, MC4, and MC5) an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000211e
更新日期：2000-12-28 00:00:00
abstract：:Three series of 4-anilino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic esters were synthesized as part of a program to study potential anti-Leishmania drugs. These compounds were obtained by a condensation reaction of 4-chloro-1H-pyrazolo[3,4-b]pyridine with several aniline derivatives. Some of them were also obtained by a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0401006
更新日期：2004-10-21 00:00:00
