Abstract:
:3',5'-Cyclic adenosine monophosphate (cAMP) is a pivotal second messenger that regulates numerous biological processes under physiological and pathological conditions, including cancer, diabetes, heart failure, inflammation, and neurological disorders. In the past, all effects of cAMP were initially believed to be mediated by protein kinase A (PKA) and cyclic nucleotide-regulated ion channels. Since the discovery of exchange proteins directly activated by cyclic adenosine 5'-monophosphate (EPACs) in 1998, accumulating evidence has demonstrated that the net cellular effects of cAMP are also regulated by EPAC. The pursuit of the biological functions of EPAC has benefited from the development and applications of a growing number of pharmacological probes targeting EPACs. In this review, we seek to provide a concise update on recent advances in the development of chemical entities including various membrane-permeable analogues of cAMP and newly discovered EPAC-specific ligands from high throughput assays and hit-to-lead optimizations.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Chen H,Wild C,Zhou X,Ye N,Cheng X,Zhou Jdoi
10.1021/jm401425esubject
Has Abstractpub_date
2014-05-08 00:00:00pages
3651-65issue
9eissn
0022-2623issn
1520-4804journal_volume
57pub_type
杂志文章,评审abstract::The inhibitory activity of 1058 inhibitors of the title enzymes has been formulated in 13 equations correlating chemical structure with inhibitory potency. Two types of regions in enzymes have been defined by means of pi and molar refractivity constants. The use of indicator variables has been extensively developed to...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00223a015
更新日期:1976-01-01 00:00:00
abstract::Anthrax lethal factor (LF) is a critical virulence factor in the pathogenesis of anthrax. A structure-activity relationship (SAR) of potential lethal factor inhibitors (LFi) is presented in which the zinc-binding group (ZBG), linker, and backbone moieties for a series of hydroxypyrone-based compounds were systematical...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm8013212
更新日期:2009-02-26 00:00:00
abstract::From a micromolar high throughput screening hit 7, the successful complementary application of a chemogenomic approach and of a scaffold hopping exercise rapidly led to a low single digit nanomolar human vasopressin 1a (hV1a) receptor antagonist 38. Initial optimization of the mouse V1a activities delivered suitable t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm501745f
更新日期:2015-03-12 00:00:00
abstract::Thymidine phosphorylase plays an important role in angiogenesis, which is an attractive target for therapy of cancer and other diseases. In our continuous effort to develop novel inhibitors of thymidine phosphorylase, we have discovered that 6-halouracils substituted at position C5 by certain hydrophobic groups exhibi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm070644i
更新日期:2007-11-29 00:00:00
abstract::Tocainide and related optically active chiral alpha-aminoanilides were synthesized and tested in vivo via the hot plate test to evaluate their central analgesic action. The aims of the study were to verify if a) the increase in lipophilicity, obtained by the introduction of an alkyl group on the steric center (3f-i), ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm061078e
更新日期:2007-04-19 00:00:00
abstract::We synthesized 5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid (14), a trifluoromethyldiazirine-containing derivative of general anesthetic mephobarbital, separated the racemic mixture into enantiomers by chiral chromatography, and determined the configuration of the (+)-enantiomer as S by X-ray...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm300631e
更新日期:2012-07-26 00:00:00
abstract::N-[2-Hydroxy-5-[2-(methylamino)ethyl]phenyl]methanesulfonamide (SK&F 102652) has been prepared and characterized pharmacologically. It is a potent agonist with an EC50 of 25 nM at alpha 1-adrenoceptors as determined in the isolated perfused rabbit ear artery. On the presynaptic alpha 2-adrenoceptors of the guinea pig ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00380a017
更新日期:1985-02-01 00:00:00
abstract::Anthelmintic efficacies of a series of 6-substituted methyl imidazo[1,2-alpha]pyridine-2-carbamates were compared to similarly substituted benzimidazole-2-carbamates. With only one exception, methyl 6-benzoylimidazo[1,2-alpha]pyridine-2-carbamate, both classes of compounds exhibited similar activity vs. Nematospiroide...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00144a030
更新日期:1981-12-01 00:00:00
abstract::On the basis of our previous observation that N1-alkyl substituted chlorpropamide derivatives when administered to rats nonenzymatically eliminated n-propyl isocyanate, a known inhibitor of aldehyde dehydrogenase (AlDH), we have synthesized other latentiated n-propyl isocyanates as in vivo inhibitors of AlDH. N1-Allyl...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00050a018
更新日期:1994-11-25 00:00:00
abstract::A series of 42 6-arylpyrrolo[2,1-d][1,5]benzothiazepines, which we have recently described as selective ligands of the mitochondrial benzodiazepine receptor (MBR) (Fiorini I.; et al. J. Med. Chem. 1994, 37, 1427-1438), have been investigated using the comparative molecular field analysis (CoMFA) approach. The resultin...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00050a007
更新日期:1994-11-25 00:00:00
abstract::To better understand the difficulties surrounding the identification of novel antibacterial compounds from corporate screening collections, physical properties of ∼3200 antibacterial project compounds with whole cell activity against Gram-negative or Gram-positive pathogens were profiled and compared to actives found ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm501552x
更新日期:2014-12-11 00:00:00
abstract::A series of triarylethylene compounds related to 4-hydroxyclomiphene (2) in which the vinyl Cl substituent was replaced by ethyl (5), Br (6), H (7), CN (8), or NO2 (9) substituents were synthesized to facilitate studies of the molecular actions of synthetic nonsteroidal antiestrogens. The relative binding affinities o...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00162a014
更新日期:1986-12-01 00:00:00
abstract::We present an RP-HPLC method, for the determination of logPoct values for neutral drugs, which combines ease of operation with high accuracy and which has been shown to work for a set of 36 molecules comprised largely of drugs. The general features of the method are as follows: (i) compound sparing (< or = 1 mL of a 3...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0000822
更新日期:2000-07-27 00:00:00
abstract::Antibiotic resistance is one of the biggest threats to public health, and new antibacterial agents hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Utilizing dimerization strategy, we rationally designed and efficiently synthesized a new series of small molecule ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b01704
更新日期:2018-04-12 00:00:00
abstract::Thyroid hormone analogues, polychlorinated biphenyls (PCBs), and their derivatives were shown to bind specifically to thyroxine-specific binding sites in rat liver nuclear extracts. The structure-binding relationship for thyroxine binding prealbumin was qualitatively similar to that for the nuclear receptor. In genera...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00384a014
更新日期:1987-01-01 00:00:00
abstract::A series of methanoprolinenitrile-containing dipeptide mimetics were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV (DPP-IV). The catalytic action of DPP-IV is the principle means of degradation of glucagon-like peptide-1, a key mediator of glucose-sti...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049924d
更新日期:2004-05-06 00:00:00
abstract::A range of cis- and trans-3-substituted 1-aminocyclobutane-1-carboxylic acids has been synthesized and evaluated for antagonism at excitatory amino acid receptor sites and for anticonvulsant activity. Potent and selective antagonist activity at N-methyl-D-aspartate (NMDA) receptor sites in neonatal rat motoneurones wa...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00051a005
更新日期:1994-12-09 00:00:00
abstract::Dysregulation of translation initiation factor 4E (eIF4E) activity occurs in various cancers. Mitogen-activated protein kinase (MAPK) interacting kinases 1 and 2 (MNK1 and MNK2) play a fundamental role in activation of eIF4E. Structure-activity relationship-driven expansion of a fragment hit led to discovery of dual M...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b01582
更新日期:2020-01-23 00:00:00
abstract::The binding structures of 11 human oxidosqualene cyclase inhibitors designed as cholesterol-lowering agents were determined for the squalene-hopene cyclase from Alicyclobacillus acidocaldarius, which is the only structurally known homologue of the human enzyme. The complexes were produced by cocrystallization, and the...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0211218
更新日期:2003-05-22 00:00:00
abstract::We evaluated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that not only were shown to be highly selective agonists for ERRγ but also exhibited enhanced pharmacokinetic profile compared with 3 (GSK5182). 6g and 10b had com...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b01204
更新日期:2016-11-23 00:00:00
abstract::The first example of vinca derivatives 16-18 able to modulate P-glycoprotein (Pgp) efflux activity is reported. They were elaborated in two steps from vinorelbine 3 (VLN) by a modification of the velbenamine moiety. These compounds were able to decrease efficiently Pgp mediated influx and efflux of rhodamine-123 (Rho)...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b00525
更新日期:2016-12-08 00:00:00
abstract::The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihydrocoumarino[3,4-f]quinoline core 1 is the key for progestational activities. The structure-activity relation...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9705768
更新日期:1998-01-29 00:00:00
abstract::4,4-Ditritio-(-)-nicotine (5) of high specific activity (4.7 Ci/mmol) has been synthesized from (-)-nicotine via the readily prepared 4,4-dibromocotinine (3). Scatchard analysis of the binding of 5 to the crude mitochondrial fraction of whole rat brain revealed a Ka of 4.7 X 10(6) M-1 and 13 fmol of binding sites/mg o...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00182a028
更新日期:1980-08-01 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::The synthesis and biological activity of a novel cyclic beta-sheet-type antimicrobial dehydropeptide based on gramicidin S (GS) is described. The GS analogue, containing two (Z)-(beta-3-pyridyl)-alpha,beta-dehydroalanine (DeltaZ3Pal) residues at the 4 and 4' positions (2), was synthesized by solution-phase methodologi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm061051v
更新日期:2006-12-28 00:00:00
abstract::Treatment of 14 beta-nitrocodeinone with sodium borohydride gave the codeine derivative which was reduced with zinc dust in acetic anhydride-acetic acid solution to give 14 beta-acetamidocodeine 6-acetate. 14 beta-Thiocyanatocodeinone was obtained from the reaction of thebaine with thiocyanogen and was reduced to 14 b...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00176a011
更新日期:1980-02-01 00:00:00
abstract::Acyclic nucleosides 1-[[2-hydroxy-1-(hydroxymethyl)ethoxy] methyl]-5-benzyluracil (DHPBU) (1) and 1-[[2-hydroxy-1-(aminomethyl)ethoxy]methyl]-5-benzyluracil (AHPBU) (2) have been synthesized by direct coupling of bis(trimethylsilyl)-5-benzyluracil with the corresponding chloromethyl ether, followed by removal of the b...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00145a023
更新日期:1985-07-01 00:00:00
abstract::The synthesis and sigma 1 and sigma 2 binding properties of several (+)- and (-)-2-benzyl- and 2-dimethylallyl-2'-substituted-5,9 alpha-dimethyl-6,7-benzomorphans (3 and 4) are presented. In agreement with previously reported binding data for 2-substituted 5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphans (N-substituted...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00015a022
更新日期:1995-07-21 00:00:00
abstract::The goal of this study was to design paclitaxel (PTX)-monoclonal antibody (mAb) prodrug conjugates (PTXMAbs) with the ability to deliver therapeutically significant doses of the drug to the tumor while avoiding the previously observed solubility limitations of conjugates with PTX:mAb molar ratios of >3. New PTX conjug...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm900899g
更新日期:2010-01-28 00:00:00
abstract::The enantiomers of the aminothiazole analogues of the known dopaminergic agonists apomorphine (1) and 2-aminohydroxytetralin (2) have been prepared. The absolute configurations of the enantiomers of 2,6-diaminotetrahydrobenzothiazole have been established by X-ray crystallographic analysis. Dopamine (DA) autoreceptor ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00386a009
更新日期:1987-03-01 00:00:00