Abstract:
:The sphingoid base derived class of lipids (sphingolipids) is a family of interconverting molecules that play key roles in numerous structural and signaling processes. The biosynthetic pathway of the sphingolipids affords many opportunities for therapeutic intervention: targeting the ligands directly, targeting the various proteins involved in the interconversion of the ligands, or targeting the receptors that respond to the ligands. The focus of this article is on the most advanced of the sphingosine-related therapeutics, agonists of sphingosine-1-phosphate receptor 1 (S1P1). The diverse structural classes of S1P1 agonists will be discussed and the status of compounds of clinical relevance will be detailed. An examination of how potential safety concerns are being navigated with compounds currently under clinical evaluation is followed by a discussion of the novel methods being explored to identify next-generation S1P1 agonists with improved safety profiles. Finally, therapeutic opportunities for sphingosine-related targets outside of S1P1 are touched upon.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Dyckman AJdoi
10.1021/acs.jmedchem.6b01575subject
Has Abstractpub_date
2017-07-13 00:00:00pages
5267-5289issue
13eissn
0022-2623issn
1520-4804journal_volume
60pub_type
杂志文章,评审abstract::Interesting analgesic activity approaching that of meperidine and codeine was observed in standard animal models for 8-chloro-3,4-dihydro-5-methoxy-2-pyrrolidinomethylnaphthalene (compound 7). This compound was orally effective and its analgesic activity was not reversed by the opiate antagonist, naloxone. A limited n...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00201a004
更新日期:1978-03-01 00:00:00
abstract::A series of 6-(alkylamino)-9-alkylpurines was synthesized and evaluated for the property of antagonizing the behavioral effects in animals of the dopamine agonist apomorphine. This model for identifying potential antipsychotic agents is based on the hypothesis that agents that antagonize apomorphine-induced aggressive...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm960662s
更新日期:1997-09-26 00:00:00
abstract::(-)-(2R,4R)-1-(2-Hydroxymethyl-1,3-dioxolan-4-yl)thymine (DOT) is the first thymidine kinase-activated nucleoside that is significantly active against all of the clinically significant NRTI-resistant HIV-1 mutants, including AZT (D67N/K70R/T215Y/K219Q), Tenofovir (K65R), and Lamivudine (M184V). To understand the molec...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050060l
更新日期:2005-06-16 00:00:00
abstract::Modification of the 2(S)-methylbutyryl moiety of mevinolin led to a series of side chain ester derivatives. A systematic exploration of the structure-activity relationships showed that the introduction of an additional aliphatic group on the carbon alpha to the carbonyl group increased potency. This observation led to...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00155a040
更新日期:1986-05-01 00:00:00
abstract::Six new analogues of 1α,25-dihydroxy-19-norvitamin D(3) (3a-4b, 5, and 6) were prepared by a convergent synthesis applying the Wittig-Horner reaction as a key step. The influence of methyl groups at C-22 on their biological activity was examined. It was established that both in vitro and in vivo activity is strongly d...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm300187x
更新日期:2012-05-10 00:00:00
abstract::A novel lysine-based trifunctional chelate 3 was designed, synthesized, and characterized and bears both a chelating moiety (CHX-A' ') for sequestering radiometals (86Y or 111In) and the near-infrared dye Cy5.5 for dual modality PET (or SPECT) and fluorescence imaging, respectively. Successful conjugation of 3 to the ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm070657w
更新日期:2007-09-20 00:00:00
abstract::Although the majority of proteins used for biomedical research are produced using living systems such as bacteria, biological means for producing proteins can be advantageously complemented by protein semisynthesis or total chemical synthesis. The latter approach is particularly useful when the proteins to be produced...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c01082
更新日期:2020-12-24 00:00:00
abstract::Evidence indicating that modifications at the 5- and 10-positions of classical folic acid antimetabolites lead to compounds with favorable differential membrane transport in tumor vs. normal proliferative tissue prompted an investigation of 5-alkyl-5-deaza analogues. 2-Amino-4-methyl-3,5-pyridinedicarbonitrile, prepar...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00156a029
更新日期:1986-06-01 00:00:00
abstract::Homology modeling of G-protein-coupled seven-transmembrane receptors (GPCRs) remains a challenge despite the increasing number of released GPCR crystal structures. This challenge can be attributed to the low sequence identity and structural diversity of the ligand-binding pocket of GPCRs. We have developed an optimize...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm400307y
更新日期:2013-06-13 00:00:00
abstract::The five dopamine receptor subtypes (D1-5) are activated by the endogenous catecholamine dopamine. Sustained research has sought to identify selective ligands for receptor subtypes. In particular, activation of the D1 receptor has attracted attention due to its promising role in neurological diseases. Initial attempts...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.8b01767
更新日期:2019-01-10 00:00:00
abstract::Activators of nuclear factor-erythroid 2-related factor 2 (NRF2) could lead to promising therapeutics for prevention and treatment of oxidative stress and inflammatory disorders. Ubiquitination and subsequent degradation of the transcription factor NRF2 is mediated by Kelch-like ECH-associated protein-1 (KEAP1). Inhib...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b01133
更新日期:2018-09-13 00:00:00
abstract::A series of cis and trans bicyclic lactones was prepared as congeners of podophyllotoxin (1) and evaluated as antimitotic agents both in cell cultures grown in vitro and in an in vitro protein binding assay. All compounds displayed insignificant activity-a result which may reflect insufficient structural similarity to...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00223a025
更新日期:1976-01-01 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::To design and synthesize new potent and selective antagonists of the human A(3) adenosine receptor, pharmacophoric hypotheses were generated with the software Catalyst for a comprehensive set of compounds retrieved from previous literature. Three of these pharmacophores were used to drive the optimization of a molecul...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm051112+
更新日期:2006-07-13 00:00:00
abstract::The photoswitchable N-terminal diazo and triazene-dipeptide aldehydes 8a-d, 10a,b, and 17a,b present predominantly as the (E)-isomer, which purportedly binds deep in the S3 pocket of calpain. All compounds are potent inhibitors of m-calpain, with 8b being the most active (IC50 of 35 nM). The diazo-containing inhibitor...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm061455n
更新日期:2007-06-14 00:00:00
abstract::HIV-1 replication has been inhibited by using a compound able to target the human cellular cofactor DEAD-box ATPase DDX3, essential for HIV-1 RNA nuclear export. This compound, identified by means of a computational protocol based on pharmacophoric modeling and molecular docking calculations, represents the first smal...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm8008844
更新日期:2008-11-13 00:00:00
abstract::Enantiomerically pure (+)- and (-)-carbocyclic thymidine, (-)-carbocyclic 3'-epi-thymidine, (+)-carbocyclic 3'-deoxy-3'-azidothymidine, (+)-carbocyclic 2,3'-O-anhydrothymidine, (+)-carbocyclic 3'-O,6'-methylenethymidine, and (+)-(6'S)-carbocyclic 6'-methylthymidine were synthesized in a stereospecific manner from comm...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00167a011
更新日期:1990-05-01 00:00:00
abstract::The crystal and molecular structure of metyrapone, a powerful inhibitor of certain cytochromes P-450, is described. Cytochrome P-450 enzymes are involved in metabolic processes, including those activating insecticides, drugs, and carcinogens. Metyrapone inhibits both the adrenal cytochrome P-450 catalyzing 11-beta-hyd...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00363a008
更新日期:1983-09-01 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::The ability of a series of substituted kynurenic acids, thienopyridinonecarboxylic acids, and related compounds to inhibit the binding of nerve growth factor (NGF) to the p75 NGF receptor (NGFR) was evaluated in a radioligand binding assay that utilized a biotinylated derivative of the extracellular domain of p75 NGFR...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00022a008
更新日期:1995-10-27 00:00:00
abstract::Quantitative structure-activity studies were carried out on a series of N-isopropylaryl hydrazides which inhibits monoamine oxidase (MAO). The inhibitory potencies of these compounds of MAO were found to correlate with the electron-withdrawing capacity of the aryl ring substituents as estimated by both empirical Hamme...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00227a005
更新日期:1976-05-01 00:00:00
abstract::A series of novel 2-substituted acetylenic pyrrolidines and piperidines related to oxotremorine (1) were prepared and evaluated in vitro as muscarinic cholinergic agents at brain M1 and M2 receptors. One analogue, 3-(2-oxo-1-pyrrolidinyl)-1-[2(R)-pyrrolidinyl]-1-propyne hydrogen oxalate (6a), was found to be a partial...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00087a008
更新日期:1992-05-01 00:00:00
abstract::N(α)-Boc-l-Asp(OBn)-l-Lys(Z)-OtBu (reversin 121, 1), an inhibitor of the P-gp ABC transporter, was used to conceive compounds inhibiting the drug efflux occurring through the Hoechst 33342 and daunorubicin transport sites of P-gp, respectively H and R sites. Replacement of the aspartyl residue by trans-4-hydroxy-l-pro...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm100839w
更新日期:2010-09-23 00:00:00
abstract::Histone lysine methyltransferases (HKMTs) are an important class of targets for epigenetic therapy. 1 (chaetocin), an epidithiodiketopiperazine (ETP) natural product, has been reported to be a specific inhibitor of the SU(VAR)3-9 class of HKMTs. We have studied the inhibition of the HKMT G9a by 1 and functionally rela...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm401063r
更新日期:2013-11-14 00:00:00
abstract::Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular diseases, obesity, and diabetes. Medications targeted to PPARs have been established to treat hyperlipidemia (fibrates) and insulin resistanc...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0502844
更新日期:2005-08-25 00:00:00
abstract::Details of the interaction between HIV-1 reverse transcriptase and non-nucleoside inhibitors (NNRTIs) have been elucidated using a biosensor-based approach. This initial study was performed with HIV-1 reverse transcriptase mutant K103N, the phenethylthioazolylthiourea compound (PETT) MIV-150, and the three NNRTIs lice...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0504048
更新日期:2006-04-20 00:00:00
abstract::Reaction of 26 aromatic/heterocyclic sulfonamides containing amino, imino, hydrazino, or hydroxyl groups with Boc-Gly, Boc-Sar, TrS-Crt, or Boc-Gly-Gly (Sar = sarcosine, N-Me-Gly; Crt = creatine, N-amidinosarcosine; TrS = tritylsulfenyl; Boc = tert-butoxycarbonyl) in the presence of carbodiimide derivatives afforded a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9901879
更新日期:1999-09-09 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::Structural simplification of an antimitotic natural product podophyllotoxin with mimetic heterocyclic scaffolds constructed using multicomponent reactions led to the identification of compounds exhibiting low nanomolar antiproliferative and apoptosis-inducing properties. The most potent compounds were found in the dih...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm200410r
更新日期:2011-06-23 00:00:00
abstract::A series of analogues of the fungal peptaibol type metabolite ampullosporin A containing modifications in the C and N terminus as well as alpha-aminoisobutyric acid (Aib) substitutions in different positions of the peptide were synthesized by solid phase synthesis using the 9-fluorenylmethyloxycarbonyl strategy. Depen...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0208018
更新日期:2002-06-20 00:00:00