Abstract：
:Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the rate-limiting step in the kynurenine pathway of tryptophan metabolism, which is involved in immunity, neuronal function, and aging. Its implication in pathologies such as cancer and neurodegenerative diseases has stimulated the development of IDO1 inhibitors. However, negative phase III clinical trial results of the IDO1 inhibitor epacadostat in cancer immunotherapy call for a better understanding of the role and the mechanisms of IDO1 inhibition. In this work, we investigate the molecular inhibition mechanisms of four known IDO1 inhibitors and of two quinones in detail, using different experimental and computational approaches. We also determine for the first time the X-ray structure of the highly efficient 1,2,3-triazole inhibitor MMG-0358. Based on our results and a comprehensive literature overview, we propose a classification scheme for IDO1 inhibitors according to their inhibition mechanism, which will be useful for further developments in the field.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Röhrig UF,Reynaud A,Majjigapu SR,Vogel P,Pojer F,Zoete Vdoi
10.1021/acs.jmedchem.9b00942subject
Has Abstractpub_date
2019-10-10 00:00:00pages
8784-8795issue
19eissn
0022-2623issn
1520-4804journal_volume
62pub_type
杂志文章abstract：:An atom economic and stereoselective synthesis of several spiro-piperidin-4-ones through 1,3-dipolar cycloaddition of azomethine ylides generated in situ from isatin and alpha-amino acids viz . proline, phenylglycine, and sarcosine to a series of 1-methyl-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones is des...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800545k
更新日期：2008-09-25 00:00:00
abstract：:Novel heteroatom-incorporated antofine and cryptopleurine analogues were designed, synthesized, and tested against a panel of five cancer cell lines. Two new S-13-oxo analogues (11 and 16) exhibited potent cell growth inhibition in vitro (GI(50): 9 nM and 20 nM). Interestingly, both compounds displayed improved select...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200330s
更新日期：2011-07-28 00:00:00
abstract：:A series of novel compounds having a benzothiazoline skeleton was studied for their structure-activity relationship (SAR) with respect to Ca2+ antagonistic activity. As test compounds, analogues of 3-acyl-2-arylbenzothiazolines (3) were synthesized. Benzothiazoline derivatives (3) exerted higher Ca2+ antagonistic acti...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00400a006
更新日期：1988-05-01 00:00:00
abstract：:Di-tert-butyl (E)-4,4'-stilbenedicarboxylate and tert-butyl 4-vinylbenzoate were copolymerized with maleic anhydride and tert-butyl 4-maleimidobenzoate, individually and respectively. After conversion into polyanions, these four copolymers exhibited activity against four HIV-1 strains: IIIb, BaL, JR-CSF, and 92UG037. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm401913w
更新日期：2014-08-14 00:00:00
abstract：:Two compounds, analogues of cephalexin with 2- and 4-pyridone groups at C-3, were prepared. Biological evaluation found the compounds to exhibit activity against Gram-positive and Gram-negative organisms in vitro and in vivo. The compounds were only active in vivo on subcutaneous administration. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00197a026
更新日期：1979-11-01 00:00:00
abstract：:The hPepT1-mediated transport properties of a series of 11 synthesized beta- and gamma-peptides have been studied in Caco-2 cells. The results show that several of the compounds interact with the peptide transporter, but only two beta-dipeptides act as substrates and are transported across the cell monolayers. These t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070148u
更新日期：2007-10-18 00:00:00
abstract：:New analogues of flavone-8-acetic acid were synthesized, bearing an alkoxy group in position 3 and different substituents on the benzene ring in position 2 of the flavone nucleus. The compounds were tested for direct cytotoxicity against four human tumor cell lines and for indirect antitumor effects by measuring their...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030771o
更新日期：2003-08-14 00:00:00
abstract：:The natural retinoid 9-cis-retinoic acid is an activating ligand for both the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are members of the retinoid/thyroid hormone/steroid hormone family of nuclear receptor proteins that activate gene transcription through specific response elements. Th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00017a021
更新日期：1995-08-18 00:00:00
abstract：:Selective CCK-A agonist activity has been reported to induce satiety in a variety of animals, including man, and thereby suggests a therapeutic role for CCK in the management of obesity. To date, three general classes of CCK-A agonists have been reported, the full-length, sulfated hepta- and hexapeptides, a series of ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990252e
更新日期：2000-06-15 00:00:00
abstract：:Syntheses of several tripeptide analogues of leupeptin containing C-terminal argininal, lysinal, or ornithinal units are presented. The synthetic analogues were tested as inhibitors of trypsin, plasmin, and kallikrein. (Benzyloxycarbonyl)-L-leucyl-L-leucyl-L-argininal (2a) was significantly less effective as an inhibi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00163a014
更新日期：1990-01-01 00:00:00
abstract：:Several N-2 substituted 1-methyl-1-(4-tolylsulfonyl)hydrazines were synthesized and evaluated for antineoplastic activity against the L1210 leukemia and the B16 melanoma. The most active compound to emerge from this study, 2-(methylsulfonyl)-1-methyl-1-(4-tolylsulfonyl)hydrazine, produced maximum percent T/C values wi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00157a033
更新日期：1986-07-01 00:00:00
abstract：:The structural features of a new class of non-nucleoside HIV-1 reverse transcriptase inhibitors (3) are presented. Comparison of the structural and electronic properties with those of TIBO (1) and Nevirapine (2) yields a common three-dimensional model. This model permits the improvement of the lead compound 3 by chemi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00058a009
更新日期：1993-03-19 00:00:00
abstract：:Dihydrocodeinone oxime (1) under Beckmann rearrangement conditions gave a product (2) that facilitated the preparation of (-)-11 alpha-substituted 1,2,3,4,5,6-hexahydro-6 alpha,7-(methyleneoxy)-2,6-methano-3-benzazocines, a hitherto little-examined series of morphine partial structures. Compounds 7a and 12 gave good l...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00160a022
更新日期：1986-10-01 00:00:00
abstract：:A systematic investigation of the impact of spermidine analogues both in vitro and in vivo is described. The study characterizes the effects of these analogues on L1210 cell growth, polyamine pools, ornithine decarboxylase, S-adenosyl-L-methionine decarboxylase, spermidine/spermine N1-acetyltransferase, the maintenanc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960849j
更新日期：1997-05-09 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：:The discovery of a pyrrolopyrimidine class of LIM-kinase 2 (LIMK2) inhibitors is reported. These LIMK2 inhibitors show good potency in enzymatic and cellular assays and good selectivity against ROCK. After topical dosing to the eye in a steroid induced mouse model of ocular hypertension, the compounds reduce intraocul...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm901226j
更新日期：2009-11-12 00:00:00
abstract：:A new class of acyclic adenosine analogues is described which exhibit broad-spectrum antiviral activity and are apparently targeted at S-adenosyl-L-homocysteine hydrolase. The compounds are all alkyl (i.e., methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methylpropyl, tert-butyl, 1-pentyl, 3-methylbutyl, 1-octy...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00381a004
更新日期：1985-03-01 00:00:00
abstract：:A series of pyridinyltetrahydropyridine derivatives was synthesized and evaluated as adrenoceptor and tetrabenazine antagonists. 4-(3-Fluoro-2-pyridinyl)-1,2,5,6-tetrahydropyridine proved to be the most potent and selective alpha 2-adrenoceptor antagonist of the series as measured in vitro by displacement of [3H]cloni...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00375a017
更新日期：1984-09-01 00:00:00
abstract：:The importance of steric factors in quantitative structure-activity relationships involving steroid hormones is discussed. a variety of steric parameters, such as parachlor, molecular volume, van der Waals volume, and including difference and squared steric terms, is explored in an attempt to find preferred forms for...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00228a002
更新日期：1976-06-01 00:00:00
abstract：:N delta-Acyl derivatives of the potent folylpolyglutamate synthetase (FPGS) inhibitor N alpha-(4-amino-4-deoxypteroyl)-L-ornithine (APA-L-Orn) were synthesized from N alpha-(4-amino-4-deoxy-N10-formylpteroyl)-L-ornithine by reaction with an N-(acyloxy)succinimide or acyl anhydride, followed by deformylation with base....
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00402a013
更新日期：1988-07-01 00:00:00
abstract：:Structure dependent efficacy studies in the field of selective D4 ligands led to the 2-aminomethyl substituted azaindole 2 (FAUC 213) that displayed strong D4 binding, high subtype selectivity, and complete antagonist properties in ligand-induced mitogenesis experiments. According to our schematic molecular model, the...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm015522j
更新日期：2001-08-16 00:00:00
abstract：:Assembly of human immunodeficiency virus (HIV-1) represents an attractive target for antiretroviral therapy which is not exploited by currently available drugs. We established high-throughput screening for assembly inhibitors based on competition of small molecules for the binding of a known dodecapeptide assembly inh...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01089
更新日期：2016-01-28 00:00:00
abstract：:A focused library approach identifying novel leads to develop a potent ORL1 antagonist is described. Beginning from a compound identified by random screening, an exploratory library that exhibited a diverse display of pharmacophores was designed. After evaluating ORL1 antagonistic activity, a highly focused library wa...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0509851
更新日期：2006-02-09 00:00:00
abstract：:Compounds acting via the neurotensin receptor type 2 (NTS2) are known to be active in animal models of acute and chronic pain. To identify novel NTS2 selective analgesics, we searched for NTS2 selective nonpeptide compounds using a FLIPR assay and identified the title compound (NTRC-824, 5) that, to our knowledge, is ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500857r
更新日期：2014-09-11 00:00:00
abstract：:A series of S-alkylated derivatives of 5-mercapto-2'-deoxyuridine have been prepared by alkylation of the preformed nucleoside. Two of these compounds, the S-propargyl and S-allyl derivatives, have shown significant antiviral activity against Herpes simplex type 1 in HeLa TK- cells but appear to be less effective in t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00179a019
更新日期：1980-05-01 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：:As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 μM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate subst...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01249
更新日期：2016-01-14 00:00:00
abstract：:Five series of pyrrolo[3,2-d]pyrimidines were synthesized and evaluated with respect to potency and selectivity toward multidrug resistance-associated protein 1 (MRP1, ABCC1). This transport protein is a major target to overcome multidrug resistance in cancer patients. We investigated differently substituted pyrrolopy...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01644
更新日期：2016-04-14 00:00:00
abstract：:Oxadiazoles are five-membered heteroaromatic rings containing two carbons, two nitrogens, and one oxygen atom, and they exist in different regioisomeric forms. Oxadiazoles are frequently occurring motifs in druglike molecules, and they are often used with the intention of being bioisosteric replacements for ester and ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm2013248
更新日期：2012-03-08 00:00:00
abstract：:The constitution of chlorpromazine has been studied in the context of its phototoxicity. Electron transfer from the side chain to the aromatic nucleus of the drug contributes to its instability to light. Even without the side chain, however, chlorophenothiazines appear to be very photolabile, so that it is unlikely th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00188a016
更新日期：1979-02-01 00:00:00
