Abstract:
:Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of novel object recognition with improved tolerability and reduced vascular toxicity over earlier PDE4 inhibitors that lack subtype selectivity. The lead compound, 28 (BPN14770), has entered midstage, human phase 2 clinical trials for the treatment of Fragile X Syndrome.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Gurney ME,Nugent RA,Mo X,Sindac JA,Hagen TJ,Fox D 3rd,O'Donnell JM,Zhang C,Xu Y,Zhang HT,Groppi VE,Bailie M,White RE,Romero DL,Vellekoop AS,Walker JR,Surman MD,Zhu L,Campbell RFdoi
10.1021/acs.jmedchem.9b00193subject
Has Abstractpub_date
2019-05-23 00:00:00pages
4884-4901issue
10eissn
0022-2623issn
1520-4804journal_volume
62pub_type
杂志文章abstract::The pyridine C-nucleosides 5-beta-D-ribofuranosylnicotinamide and its N-methylpyridinium derivative (1 and 2), which are isosteric and isoelectronic, respectively, to nicotinamide nucleoside were synthesized. Condensation of 3-bromo-5-lithiopyridine with 2,4:3,5-di-O-benzylidene-D-aldehydoribose (7) afforded an allo/a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00388a030
更新日期:1987-05-01 00:00:00
abstract::Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-mediated transcription factor with roles in glucose, lipid, and lipoprotein homeostasis, and PPARγ ligands are expected have therapeutic potential in these as well as other areas. We report here the design, synthesis, crystallographic analysis, and c...
journal_title:Journal of medicinal chemistry
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更新日期:2011-01-13 00:00:00
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pub_type: 杂志文章
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更新日期:2014-11-13 00:00:00
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journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm040817t
更新日期:2004-12-16 00:00:00
abstract::The ruthenium complex, trans-[Ru(Bz)(NH 3) 4SO 2](CF 3SO 3) 2 1, Bz = benznidazole ( N-benzyl-2-(2-nitro-1 H-imidazol-1-yl)acetamide), is more hydrosoluble and more active (IC 50try/1 h = 79 +/- 3 microM) than free benznidazole 2 (IC 50try/1 h > 1 mM). 1 also exhibits low acute toxicity in vitro (IC 50macrophages > 1 ...
journal_title:Journal of medicinal chemistry
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doi:10.1021/jm701306r
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abstract::Several new phospholipid-ara-C conjugates have been prepared and tested as prodrugs of the parent ara-C. The new derivative include ara-CMP-L-dipalmitin, ara-CDP-L-distearin, ara-CDP-L dimyristin, ara-CDP-L-diolein, and the radioactively labeled derivative ara-CDP-L-di[1-14C]palmitin. In addition, the unusually stable...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00353a010
更新日期:1982-11-01 00:00:00
abstract::We have synthesized and evaluated azaquinoxalinediones 3a-c for their activity in inhibiting [3H]AMPA binding from rat whole brain. It was found that the azaquinoxalinedione nucleus functions as a bioisostere for quinoxalinedione in AMPA receptor binding. The detailed structure-activity relationships of 6- and/or 7-su...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm950304+
更新日期:1996-03-15 00:00:00
abstract::Antagonizing the robust stimulation of food intake by neuropeptide Y represents a new potential therapeutic approach for the treatment of obesity. Earlier pharmacological studies have pointed to the Y1 and Y5 receptors as the most likely mediators of the NPY orexigenic response. In this paper, we describe a new series...
journal_title:Journal of medicinal chemistry
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doi:10.1021/jm030490g
更新日期:2004-04-22 00:00:00
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journal_title:Journal of medicinal chemistry
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doi:10.1021/acs.jmedchem.9b01079
更新日期:2019-10-24 00:00:00
abstract::Three monomethylated derivatives of 4'-hydroxyacetanilide (acetaminophen) were prepared in order to compare their cytotoxic potential and analgesic activity with that of acetaminophen. Only 4'-hydroxy-N-methylacetanilide (N-methylacetaminophen) was devoid of cytotoxic effects to hepatic tissue of mice. Results of comp...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00159a029
更新日期:1986-09-01 00:00:00
abstract::Structural genomics will yield an immense number of protein three-dimensional structures in the near future. Automated theoretical methodologies are needed to exploit this information and are likely to play a pivotal role in drug discovery. Here, we present a fully automated, efficient docking methodology that does no...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm020830i
更新日期:2002-10-10 00:00:00
abstract::Human immunodeficiency virus (HIV) infection is now pandemic. Targeting HIV-1 reverse transcriptase (HIV-1 RT) has been considered as one of the most successful targets for the development of anti-HIV treatment. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a defin...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b00843
更新日期:2019-05-23 00:00:00
abstract::Glycosylated β-endorphin analogues of various amphipathicity were studied in vitro and in vivo in mice. Opioid binding affinities of the O-linked glycopeptides (mono- or disaccharides) and unglycosylated peptide controls were measured in human receptors expressed in CHO cells. All were pan-agonists, binding to μ-, δ-,...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm400879w
更新日期:2014-03-27 00:00:00
abstract::A series of N alpha-(arylsulfonyl)-L-arginine amide derivatives with substituted or unsubstituted naphthalene and heterocyclic compounds as the N alpha-substituent was prepared and tested as inhibitors of the clotting activity of thrombin. N-n-Butyl and N-n-butyl-N-methyl derivatives of N alpha-dansyl-L-arginine amide...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00182a004
更新日期:1980-08-01 00:00:00
abstract::By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective, and cell-activ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b00522
更新日期:2019-10-24 00:00:00
abstract::The pharmaceutical industry has recognized that many drug-like molecules can self-aggregate in aqueous media and have physicochemical properties that skew experimental results and decisions. Herein, we introduce the use of a simple NMR strategy for detecting the formation of aggregates using dilution experiments that ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm400535b
更新日期:2013-06-27 00:00:00
abstract::A primary goal of lead optimization is to identify compounds with improved absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. A number of reports have linked computed molecular properties to desirable in vivo ADMET outcomes, but a significant limitation of these analyses is the failure t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm300684u
更新日期:2012-07-26 00:00:00
abstract::Valproic acid (VPA) is a major antiepileptic drug (AED); however, its use is limited by two life-threatening side effects: teratogenicity and hepatotoxicity. Several constitutional isomers of VPA and their amide and urea derivatives were synthesized and evaluated in three different anticonvulsant animal models and a m...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm7009233
更新日期:2007-12-13 00:00:00
abstract::CrtN has been identified as an attractive and druggable target for treating pigmented Staphylococcus aureus infections. More than 100 new compounds were synthesized, which target the overwhelming the defects of the CrtN inhibitor 1. Analogues 23a and 23b demonstrated a significant activity against pigmented S. aureus ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b01300
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abstract::Basic derivatives of 6,7-dihydroindolo[1,7-ab][1]benzazepine and 6H-indolo[7,1-cd][1,5]benzoxazepine incorporating the imipramine basic side chain were synthesized and screened for antidepressant activity in mice. With few exceptions, the compounds unsubstituted at C-2 antagonized reserpine-induced ptosis and hypother...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00224a003
更新日期:1976-02-01 00:00:00
abstract::The preparation of a series of indole N-acyl and N-carbamic esters of (+/-)-alpha-5-[1-(indol-3-yl)ethyl]-2-methylamino-delta2-thiazolin-4-one (1) is reported. These derivatives were synthesized as potential water-soluble precursors of the antiviral thiazolinone 1, for evaluation by intranasal administration against i...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00188a013
更新日期:1979-02-01 00:00:00
abstract::The proposed sst(1) pharmacophore (J. Med. Chem. 2005, 48, 523-533) derived from the NMR structures of a family of mono- and dicyclic undecamers was used to design octa-, hepta-, and hexamers with high affinity and selectivity for the somatostatin sst(1) receptor. These compounds were tested for their in vitro binding...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm801314f
更新日期:2009-05-14 00:00:00
abstract::A group of oligopeptides has been synthesized that are structurally related to the natural antiviral antitumor agents netropsin and distamycin but which bear alkylating functions. Cytostatic activity against both human and murine tumor cell lines as well as their in vitro activity against a range of viruses is reporte...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00397a012
更新日期:1988-02-01 00:00:00
abstract::Detailed molecular models of the free C1B domain of protein kinase C-gamma (PKC-gamma) and the C1B domain with its activator phorbol-12-myristate-13-acetate (PMA) in water solution and in the presence of dipalmitoylphosphatidylcholine (DPPC) bilayer are presented. Molecular dynamics of the free C1B domain reveals hydr...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049786s
更新日期:2004-12-16 00:00:00
abstract::Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a serine/threonine kinase implicated in the regulation of many biological processes. A fragment-based lead discovery approach was used to generate potent and selective MAP4K4 inhibitors. The fragment hit pursued in this article had excellent ligand ef...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm500155b
更新日期:2014-04-24 00:00:00
abstract::The optimization of a series of aminooxazoline xanthene inhibitors of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aβ lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm501266w
更新日期:2014-12-11 00:00:00
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journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00150a024
更新日期:1985-12-01 00:00:00
abstract::The alcohol-abuse deterrent disulfiram (DSF) is shown to have a highly selective toxicity against melanoma in culture, inducing a largely apoptotic response, with much lower toxicity against several other cell lines. Melanoma cell lines derived from different stages (radial, vertical, and metastatic phase) were all se...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049568z
更新日期:2004-12-30 00:00:00
abstract::The first nonpeptidic, noncovalent inhibitors of the cysteine protease cathepsin S (CatS) are described. Electronic database searching using the program DOCK generated a screening set of potential CatS inhibitors from which two lead structures were identified as promising starting points for a drug discovery effort. L...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0496133
更新日期:2004-09-23 00:00:00
abstract::C-terminal fragment analogues of the leech anticoagulant peptide hirudin represent a unique class of thrombin inhibitors that blocks thrombin's cleavage of fibrinogen but does not block the catalytic site of thrombin. In this paper, a series of synthetic peptides were prepared by solid-phase methodology to determine t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00400a020
更新日期:1988-05-01 00:00:00