Abstract：
:Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimization of a series of phenyl sulfonamides that exhibit a novel mode of binding to non-bromodomain and extra terminal domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule, we report its divergent optimization toward the ATPase family AAA domain containing 2 (ATAD2) and cat eye syndrome chromosome region, candidate 2 (CECR2) domains. This work concludes with the identification of ( R )-55 (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Lucas SCC,Atkinson SJ,Bamborough P,Barnett H,Chung CW,Gordon L,Mitchell DJ,Phillipou A,Prinjha RK,Sheppard RJ,Tomkinson NCO,Watson RJ,Demont EHdoi
10.1021/acs.jmedchem.0c00021subject
Has Abstractpub_date
2020-05-28 00:00:00pages
5212-5241issue
10eissn
0022-2623issn
1520-4804journal_volume
63pub_type
杂志文章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：:As a mitotic-specific target widely deregulated in various human cancers, polo-like kinase 1 (Plk1) has been extensively explored for anticancer activity and drug discovery. Although multiple catalytic domain inhibitors were tested in preclinical and clinical studies, their efficacies are limited by dose-limiting cyto...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01669
更新日期：2020-11-25 00:00:00
abstract：:Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction networ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01290
更新日期：2020-11-25 00:00:00
abstract：:This work reports on the synthesis, characterization, and in vitro cytotoxic activity of some new platinum(II), palladium(II), and gold(III) derivatives of methylsarcosinedithiocarbamate and its S-methyl ester, to study their behavior as potential antitumor agents. The biological activity of these compounds, as determ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049191x
更新日期：2005-03-10 00:00:00
abstract：:Although there are many estrogen receptor antagonists with improved tissue selectivity profiles compared with tamoxifen, optimal tissue selectivity has not yet been demonstrated. As such there is still a need for additional diversity and new chemical scaffolds to allow for exploration of improved tissue selectivity. H...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020536q
更新日期：2003-04-10 00:00:00
abstract：:The dopamine D4 receptor garnered a great deal of interest in the early 1990s when studies showed the atypical antipsychotic clozapine possessed higher affinity for D4, relative to other dopamine receptor subtypes, and that this activity might underlie the unique clinical efficacy of clozapine. Unfortunately, D4 antag...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.7b00151
更新日期：2017-09-14 00:00:00
abstract：:The discovery of 8-(5,8-dichloro-1,2,3,4-tetrahydro-naphthalen-2-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1a, as a high-affinity ligand for the human ORL1 (orphanin FQ/nociceptin) receptor led to the synthesis of a series of optimized ligands. These compounds exhibit high affinity for the human ORL1 receptor, e...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm991129q
更新日期：2000-04-06 00:00:00
abstract：:C-Jun NH2 terminal kinases (JNKs) are important cell signaling enzymes. JNK1 plays a central role in linking obesity and insulin resistance. JNK2 and JNK3 may be involved in inflammatory and neurological disorders, respectively. Small-molecule JNK inhibitors could be valuable tools to study the therapeutic benefits of...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060465l
更新日期：2006-07-27 00:00:00
abstract：:In previous studies we demonstrated that lipophilic (99m)Tc-labeled LTB4 antagonist 1 (RP517) accumulated in infectious foci in rabbits, but hepatobiliary clearance hampered imaging of abdominal lesions. We now report the use of cysteic acid as a pharmacokinetic modifier to improve the water solubility and renal clear...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050383h
更新日期：2005-10-06 00:00:00
abstract：:Investigation of tricyclic heterocycles related to the 2-arylpyrazolo[4,3-c]quinolin-3(5H)-ones, structures with high affinity for the benzodiazepine (BZ) receptor, led to the synthesis of 2-phenyl-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one, a compound with 4 nM binding affinity to the BZ receptor. Analogues were prep...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00105a044
更新日期：1991-01-01 00:00:00
abstract：:Novel flavagline analogues were synthesized and examined with respect to their cytotoxicity. Structural features critical to the potential of this class of anticancer natural products were unraveled. We demonstrated, in particular, that the introduction of substituants at C-2 has a deleterious effect on multidrug resi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm101318b
更新日期：2011-01-13 00:00:00
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：:Hydroxyurea, hydroxyguanidine, and some thiosemicarbazones have been shown to have anticancer and antiviral activities. One of their possible sites of action is the enzyme ribonucleotide reductase (RR). Combination of the structural features of these compounds led to the design and synthesis of the Schiff bases of N-h...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00146a022
更新日期：1985-08-01 00:00:00
abstract：:Coactivator-associated arginine methyltransferase 1 (CARM1) represents a valuable target for hormone-dependent tumors such as prostate and breast cancers. Here we report the enzyme and cellular characterization of the 1-benzyl-3,5-bis(3-bromo-4-hydroxybenzylidene)piperidin-4-one (7g) and its analogues 8a-l. Among them...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200453n
更新日期：2011-07-14 00:00:00
abstract：:We have rationally designed a sLe(x) mimetic based on molecular modeling, synthesized type II and type II' beta-turn dipeptides (3a,b), and evaluated their biological profiles both in vitro and in vivo. Against E-selectin-sLe(x) binding, the type II beta-turn dipeptide L-Ser-D-Glu 3a (IC50, 13 microM) and the type II'...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970262k
更新日期：1997-10-24 00:00:00
abstract：:In tissue engineering, survival of larger constructs remains challenging due to limited supply of oxygen caused by a lack of early vascularization. Controlled release of oxygen from small organic molecules represents a possible strategy to prevent cell death under anoxic conditions. A comprehensive study of methylated...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm4016137
更新日期：2013-12-27 00:00:00
abstract：:A series of 75 guanidine and 2-aminoimidazoline analogue molecules were assayed in vitro against Trypanosoma brucei rhodesiense STIB900 and Plasmodium falciparum K1. The dicationic diphenyl compounds exhibited the best activities with IC 50 values against T. b. rhodesiense and P. falciparum in the nanomolar range. Fiv...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm7013088
更新日期：2008-02-28 00:00:00
abstract：:A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500818a
更新日期：2014-08-14 00:00:00
abstract：:A new class of 2,3-diaziridinyl-1,4-naphthoquinone sulfonates (27 compounds) has been synthesized and evaluated as potential antineoplastic agents. The most active compounds, benzenesulfonate 4, p-toluenesulfonate 5, p-methoxybenzenesulfonate 7,8-quinolinesulfonate 17, and 2-thiophenesulfonate 20, in the aromatic sulf...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00127a012
更新日期：1989-07-01 00:00:00
abstract：:Five dipeptidomimetic-based model prodrugs containing ketomethylene amide bond replacements were synthesized from readily available alpha,beta-unsaturated gamma-ketoesters. The model drug (BnOH) was attached to the C-terminus or to one of the side chain positions of the dipeptidomimetic. The stability, the affinity fo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm040780c
更新日期：2004-09-09 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：:This paper describes an extended structure-activity relationships study of aminotetralin-piperazine-based hybrid molecules developed earlier for dopamine D2/D3 receptors. Various analogues as positional isomers have been developed where location of the phenolic hydroxyl group has been varied on the aromatic ring. Betw...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070860r
更新日期：2008-01-10 00:00:00
abstract：:Several 1,2-dihydro-5-(substituted phenyl)-2(1H)-pyridinones were synthesized and evaluated for inotropic activity. 1,2-Dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3- pyridinecarbonitrile (5a) and the corresponding unsubstituted analogue 14a were the most potent positive inotropic agents in this series. Alth...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00389a011
更新日期：1987-06-01 00:00:00
abstract：:We report herein the identification of the rhodium(III) complex [Rh(phq)2(MOPIP)]+ (1) as a potent and selective ATP-competitive neural precursor cell expressed, developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) inhibitor. Structure-activity relationship analysis indicated that the overall organometalli...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00250
更新日期：2017-01-12 00:00:00
abstract：:The synthesis of 5-(arylacetyl)-4-[(alkylamino)methyl]furo[3,2-c] pyridines (16-23, 26, 27) and their activities as kappa-opioid receptor agonists are described. kappa-Agonist potency was particularly sensitive to the nature of the basic moiety. In particular, in the rabbit vas deferens (kappa-specific tissue), the 3-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00040a004
更新日期：1994-07-08 00:00:00
abstract：:A number of novel dihydropyridine derivatives based upon 1, 4-dihydro-3-(methoxycarbonyl)-2, 6-dimethyl-4-(4-nitrophenyl)-5-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human alpha adrenoceptors as well as the rat L-type calcium channel. Within this comp...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980077m
更新日期：1998-07-02 00:00:00
abstract：:On-line affinity capillary electrophoresis-electrospray ionization-mass spectrometry (ACE-MS) was used for the simultaneous measurement of multiple binding constants of an all-D-tetrapeptide library to the model receptor, vancomycin. Determination of Kd values for the 19 peptides of the form Fmoc-DXYA is demonstrated....
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970578s
更新日期：1998-03-26 00:00:00
abstract：:A variety of N-(phenylsulfonyl)-N-phenylglycines 5, N-(phenylsulfonyl)-2-phenylglycines 6, and N-(phenylsulfonyl)anthranilic acids 7 were prepared as analogues of the N-(phenylsulfonyl)glycine 1 aldose reductase inhibitors. In the rat lens assay, several derivatives of 5 display greater inhibitory activity than the co...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00121a027
更新日期：1989-01-01 00:00:00
abstract：:Analogues of the antimycotic allylamine terbinafine were prepared in which the naphthalene and the tert-butyl-acetylene moieties were preserved, but the spacer between these two groups was varied, and the antifungal activity of the new compounds was evaluated. All modifications of the original spacer such as reduction...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00031a010
更新日期：1994-03-04 00:00:00
abstract：:A four-step synthesis of 2-chlorodopamine (2b) is presented as well as methods for the syntheses of the N-methyl, ethyl, and n-propyl analogues (2c-e). Compounds 2b and 2c were essentially equipotent to dopamine for increasing renal blood flow in anesthetized dogs that had been treated with the alpha-adrenergic antago...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00159a005
更新日期：1986-09-01 00:00:00
