Abstract：
:The scaffold concept was applied to systematically determine, analyze, and compare core structures of kinase inhibitors. From publicly available inhibitors of the human kinome, scaffolds and cyclic skeletons were systematically extracted and organized taking activity data, structural relationships, and retrosynthetic criteria into account. Scaffold coverage varied greatly across the kinome, and many scaffolds representing compounds with different activity profiles were identified. The majority of kinase inhibitor scaffolds were involved in well-defined yet distinct structural relationships, which had different consequences on compound activity. Scaffolds exclusively representing highly potent compounds were identified as well as structurally analogous scaffolds with very different degrees of promiscuity. Scaffold relationships presented herein suggest a variety of hypotheses for inhibitor design. Our detailed organization of the kinase inhibitor scaffold universe with respect to different activity and structural criteria, all scaffolds, and the original compound data assembled for our analysis are made freely available.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Hu Y,Bajorath Jdoi
10.1021/jm501237ksubject
Has Abstractpub_date
2015-01-08 00:00:00pages
315-32issue
1eissn
0022-2623issn
1520-4804journal_volume
58pub_type
杂志文章abstract：:Following the recent discoveries that some L-nucleosides are more or equal potent than their D-counterparts, we synthesized 2'-deoxy-2',2'-difluoro-L-erythro-pentofuranosyl nucleosides as potential antiviral agents. The target compounds were synthesized via the key intermediates 7a or 7b from L-gulono gamma-lactone. C...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970275y
更新日期：1997-10-24 00:00:00
abstract：:Understanding the "limits and boundaries" of the central nervous system (CNS) property space is a critical aspect of modern CNS drug design. Medicinal chemists are often guided by the physicochemical properties of marketed CNS drugs, which are heavily biased toward "traditional" aminergic targets and commonly describe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,收录出版
doi：10.1021/acs.jmedchem.6b01469
更新日期：2017-07-27 00:00:00
abstract：:A series of the anti-HIV nucleoside conjugates of either (1-O-alkyl) and thioether (1-S-alkyl) lipids linked by a pyrophosphate diester bond has been synthesized as micelle-forming prodrugs of the nucleosides to improve their therapeutic efficiency. These include AZT 5'-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950620o
更新日期：1996-04-26 00:00:00
abstract：:With a view to identify novel and biocompatible neuroprotectants, we designed nucleoside 5'-thiophosphate analogues, 6-11. We identified 2-SMe-ADP(α-S), 7A, as a most promising neuroprotectant. 7A reduced ROS production in PC12 cells under oxidizing conditions, IC50 of 0.08 vs 21 μM for ADP. Furthermore, 7A rescued pr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00575
更新日期：2015-11-12 00:00:00
abstract：:The arachidonic acid metabolizing enzymes cyclooxygenase-2 (COX-2) and lipoxygenases (LOXs) have been found to be implicated in a variety of cancers, including prostate cancer. To develop new therapeutic treatments, it therefore seemed interesting to design dual COX-2/5-LOX inhibitors. We report here the synthesis and...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0407761
更新日期：2004-12-02 00:00:00
abstract：:A family of analogues of des-AA(1,2,5)-[DTrp(8)/D2Nal(8)]-SRIF that contain a 4-(N-isopropyl)-aminomethylphenylalanine (IAmp) at position 9 was identified that has high affinity and selectivity for human somatostatin receptor subtype 1 (sst1). The binding affinities of des-AA(1,2,5)-[DTrp(8),IAmp(9)]-SRIF (c[H-Cys-Lys...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010037+
更新日期：2001-06-21 00:00:00
abstract：:Alkyne 40, 5-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpent-4-yn-2-ol (EC144), is a second generation inhibitor of heat shock protein 90 (Hsp90) and is substantially more potent in vitro and in vivo than the first generation inhibitor 14 (BIIB021) that co...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300810x
更新日期：2012-09-13 00:00:00
abstract：:Several new 1-substituted 3,5-dimethylpyrazoles were prepared for testing as hypoglycemic agents. A number of these containing para-substituted 1-carbonylphenylurea and para-substituted 1-carbamoylbenzenesulfonylurea derivatives were found to possess potent hypoglycemic activity. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00365a023
更新日期：1983-11-01 00:00:00
abstract：:Serotonin (5-HT) binds with nearly identical affinity at the various central 5-HT binding sites. Few agents bind with selectivity for 5-HT1A sites. The beta-adrenergic antagonist propranolol binds stereoselectively both at 5-HT1A and 5-HT1B sites (with a several-fold selectivity for the latter) and, whereas it is a 5-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00124a021
更新日期：1989-04-01 00:00:00
abstract：:Bioisosteric substitution was used as a tool to generate several new structural alternatives to the thiazolidine-2,4-dione and tetrazole heterocycles as potential antidiabetic agents. Among the initial leads that emerged from this strategy, a family of acidic azoles, isoxazol-3- and -5-ones and a pyrazol-3-one, showed...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00004a008
更新日期：1995-02-17 00:00:00
abstract：:Dideoxy- and trideoxynucleosides of 5-fluorouracil have been synthesized for antitumor evaluation. 2',5'-Dideoxy-5-fluorouridine (3) was prepared from 2'-deoxy-5-fluorouridine (1) by iodination using methyltriphenoxyphosponium iodide, followed by catalytic reduction. 1-(2',5'-Dideoxy-beta-D-threo-pentofuranosyl)5-fluo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00182a008
更新日期：1980-08-01 00:00:00
abstract：:As described in the preceding paper (Arvanitis et al. J. Med. Chem. 1999, 42), anilinopyrimidines I were identified as potent antagonists of corticotropin-releasing hormone-1 receptor (CRH1-R, also referred to as corticotropin-releasing factor, CRF1-R). Our next goal was to understand the receptor-bound conformation o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980223o
更新日期：1999-03-11 00:00:00
abstract：:Phenyl-substituted analogues of 2-[(phenylmethyl)sulfonyl]pyridine 1-oxide preemergent herbicides were examined in order to determine quantitative relationships between structure and activity against the following three weed species: switch grass (Panicum virgatum L.), barnyard grass (Echinochloa crusgalli L. Beauv.),...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00358a004
更新日期：1983-04-01 00:00:00
abstract：:If no structural information about a particular target protein is available, methods of rational drug design try to superimpose putative ligands with a given reference, e.g., an endogenous ligand. The goal of such structural alignments is, on the one hand, to approximate the binding geometry and, on the other hand, to...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm981037l
更新日期：1998-11-05 00:00:00
abstract：:Caspases are cysteine proteases that specifically cleave Asp-Xxx bonds. They are key agents in inflammation and apoptosis and are attractive targets for therapy against inflammation, neurodegeneration, ischemia, and cancer. Many caspase structures are known, but most involve either peptide or protein inhibitors, unatt...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0305523
更新日期：2004-05-06 00:00:00
abstract：:Dequalinium (4) is a potent and selective blocker of small conductance Ca2+-activated K+ channels, an important but relatively little studied class. The 4-NH2 group of dequalinium has been shown to contribute significantly to blocking potency. In this study, we have investigated further the role of the 4-NH2 group. Re...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00018a013
更新日期：1995-09-01 00:00:00
abstract：:Cyclopentenones containing a 4-(methylsulfonyl)phenyl group in the 3-position and a phenyl ring in the 2-position are selective inhibitors of cyclooxygenase-2 (COX-2). The selectivity for COX-2 over COX-1 is dramatically improved by substituting the 2-phenyl group with halogens in the meta position or by replacing the...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980642l
更新日期：1999-04-08 00:00:00
abstract：:Endosomal toll-like receptors (TLRs) 7 and 8 recognize viral single-stranded RNAs, a class of imidazoquinoline compounds, 8-oxo-adenosines, 8-aminobenzodiazepines, pyrimidines, and guanosine analogues. Substantial evidence is present linking chronic inflammation mediated specifically by TLR7 to the progression of auto...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01201
更新日期：2019-11-27 00:00:00
abstract：:A series of novel 7-[3-(1-piperidinyl)propoxy]chromenones was synthesized and tested as potential antipsychotics in several in vitro and in vivo assays. The compounds possessed good affinity for D2 receptors, together with a greater affinity for 5-HT2 receptors, a profile which has been proposed as a model for atypica...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9810396
更新日期：1998-12-31 00:00:00
abstract：:A new class of histamine analogues characterized by a 3, 3-diphenylpropyl substituent at the 2-position of the imidazole nucleus has been prepared outgoing from 4,4-diphenylbutyronitrile (4b) via cyclization of the corresponding methyl imidate 5b with 2-oxo-4-phthalimido-1-butyl acetate or 2-oxo-1,4-butandiol in liqui...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm991056a
更新日期：2000-03-23 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：:The vinyl ethers of choline and of its alpha- and beta-methyl homologues were prepared to determine their cholinergic effects and to determine whether a separation of the dual physiologic activity (nicotinic and muscarinic) reported for the vinyl ether of choline could be achieved by this modification. A literature me...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00229a015
更新日期：1976-07-01 00:00:00
abstract：:The preparation and antitubercular properties of a series of 2,8-bis(alkylaminomethyl)phenazines are described. These compounds all inhibited the growth of Mycobacterium smegmatis ATCC 607 in vitro. 2,8-Bis(dibutylaminomethyl)phenazine (5c) was also active against a lethal Mycobacterium tuberculosis H37Rv infection in...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00202a020
更新日期：1978-04-01 00:00:00
abstract：:A series of thiazolothiazepines were prepared and tested against purified human immunodeficiency virus type-1 integrase (HIV-1 IN) and viral replication. Structure-activity studies reveal that the compounds possessing the pentatomic moiety SC(O)CNC(O) with two carbonyl groups are in general more potent against purifie...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990047z
更新日期：1999-08-26 00:00:00
abstract：:Analogues of luliberin containing an alpha-azaamino acid in position 6, 9, or 10 (I--XIV) have been synthesized by the solution method of peptide synthesis. Two nonaza analogues, [D-Phe6]- and [D-Ser(But)6,des-Gly-NH2(10),Pro-ethylamide9]luliberin, were also synthesized for comparison. The ovulation-inducing activity ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00208a004
更新日期：1978-10-01 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：:Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series of N-cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines were designed, synthesized, and assayed, leading to the discovery of a benzylamine derivative (compound 4, SLL-039) as a highly sele...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00857
更新日期：2019-12-26 00:00:00
abstract：:BRD4 has recently emerged as a promising drug target. Therefore, identifying novel inhibitors with distinct properties could enrich their use in anticancer treatment. Guided by the cocrystal structure of hit compound 4 harboring a five-membered-ring linker motif, we quickly identified lead compound 7, which exhibited ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01094
更新日期：2019-09-26 00:00:00
abstract：:Among the nonclassical cannabinoids, CP-55,244 (4), which incorporates an axial 14 beta-hydroxymethyl group, is pharmacologically 30 times more potent than its prototype CP-47,497 (2) and 300 times more potent than delta 9-THC (1). It has a high degree of stereoselectivity (about 120:1) with respect to its diastereois...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960410r
更新日期：1998-01-15 00:00:00
abstract：:Fifteen quinolizidine derivatives have been tested for antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig (gp) heart tissues and to assess calcium antagonist activity. All compounds exhibited from moderate to high antiarrhythmic activity, and five of them (3, 4, 6, 13, and 15) were more active ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100298d
更新日期：2010-06-24 00:00:00
