Abstract：
:TYK2 is an emerging drug target for various human autoimmune diseases. However, discovery of selective TYK2 inhibitor over other JAK family members (i.e., JAK1, 2, 3) by targeting the catalytically active site (Janus Homologue 1 (JH1) domain) is challenging. This Viewpoint discusses the discovery of a series of N-methyl pyridazine-3-carboxamides as novel selective pseudokinase (JH2) domain binders of TYK2. A systematic structure-based optimization yielded a highly potent and selective allosteric TYK2 inhibitor candidate that is currently in phase III clinical trial for psoriasis.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Chang Y,Xu S,Ding Kdoi
10.1021/acs.jmedchem.9b01612subject
Has Abstractpub_date
2019-10-24 00:00:00pages
8951-8952issue
20eissn
0022-2623issn
1520-4804journal_volume
62pub_type
评论,杂志文章abstract：:Starting from a known inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase (IN); caffeic acid phenethyl ester (CAPE), a putative three-point pharmacophore for binding of inhibitors to IN was derived. This pharmacophore was used to search the National Cancer Institute three-dimensional (3D) structural dat...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960596u
更新日期：1997-03-14 00:00:00
abstract：:Twelve 1,4-naphthoquinones have been tested against the ascitic form of sarcoma 180 in Swiss mice. Statistical analysis shows that the most important molecular parameter determining their effectiveness in prolonging the life of mice bearing this tumor is their redox potentials. Although the toxicities of the compounds...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00358a021
更新日期：1983-04-01 00:00:00
abstract：:The 5-fluoro and 8-fluoro analogues of trimetoquinol, TMQ, have been synthesized and evaluated for beta 2- and beta 1-adrenoceptor activity in guinea pig trachea and atria, respectively. The fluoro analogues of TMQ maintained potent beta 2-adrenoceptor agonist activity but had reduced beta 1-adrenoceptor agonist activ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00384a015
更新日期：1987-01-01 00:00:00
abstract：:Establishing quantitative relationships between molecular structure and broad biological effects has been a long-standing goal in drug discovery. Evaluation of the capacity of molecules to modulate protein functions is a prerequisite for understanding the relationship between molecular structure and in vivo biological...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050494g
更新日期：2005-11-03 00:00:00
abstract：:N, N'-dihydroxybenzamdine represents a model compound for a new prodrug principle to improve the oral bioavailability of drugs containing amidine functions. The activation of the prodrug could be demonstrated in vitro by porcine and human subcellular enzyme fractions, the mitochondrial benzamidoxime reducing system, a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm701259d
更新日期：2007-12-27 00:00:00
abstract：:Tipifarnib (R115777), an inhibitor of human protein farnesyltransferase (PFT), is shown to be a highly potent inhibitor of Trypanosoma cruzi growth (ED(50) = 4 nM). Surprisingly, this is due to the inhibition of cytochrome P450 sterol 14-demethylase (CYP51, EC 1.14.13.70). Homology models of the T. cruzi CYP51 were us...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050441z
更新日期：2005-08-25 00:00:00
abstract：:Although intravenously administered antiplatelet fibrinogen receptor (GPIIb/IIIa) antagonists have become established in the acute-care clinical setting for the prevention of thrombosis, orally administered drugs for chronic use are still under development. Herein, we present details from our exploration of structure-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990418b
更新日期：1999-12-16 00:00:00
abstract：:Several 4-alkyl-1-arylpiperazines that present a tetralin moiety on the terminal part of the side chain were synthesized in order to increase the selectivity on the 5-HT1A versus D-2, alpha 1, sigma, and other 5-HT receptors. Many changes have been effected on previous structures of type 3(1-aryl-4-[3-(1,2-dihydronaph...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00006a013
更新日期：1995-03-17 00:00:00
abstract：:A series of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/p75)-binding site on HIV-1 integrase, an attractive target for antiviral chemotherapy, was prepared and screened for activity against HIV-1 infection in cell culture. Small molecules t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01473
更新日期：2019-02-14 00:00:00
abstract：:The synthesis and in vitro and in vivo antibreast and antiprostate cancers activities of novel C-4 heteroaryl 13-cis-retinamides that modulate Mnk-eIF4E and AR signaling are discussed. Modifications of the C-4 heteroaryl substituents reveal that the 1H-imidazole is essential for high anticancer activity. The most pote...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501792c
更新日期：2015-02-26 00:00:00
abstract：:Here, we report the synthesis of a designed multi-pharmacophore ligand derived from the linkage of a delta selective peptide antagonist (Dmt-Tic) and a mu/kappa morphinan agonist butorphan (MCL 101) through a two methylene spacer. The new compound MCL 450 maintains the same characteristics as those the two reference c...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0605785
更新日期：2006-09-07 00:00:00
abstract：:Lofexidine, an alpha 2-agonist, has central hypotensive activity and peripheral intestinal antisecretory activity. Analogues were synthesized with increased polarity in an attempt to prevent penetration of the blood-brain barrier. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00164a024
更新日期：1990-02-01 00:00:00
abstract：:The cytotoxicities and DNA cross-linking abilities of several alkyl-substituted diaziridinylquinones have been investigated. The cytotoxicities were determined in DT-diaphorase-rich (H460 and HT29) and -deficient (H596 and BE) cell lines. It was shown that the cytotoxicities in these cell lines correlated with the rel...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm991007y
更新日期：1999-06-17 00:00:00
abstract：:The synthesis of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones and analogues is reported. Their cytotoxic activity was evaluated according to protocols available at the National Cancer Institute (NCI), Bethesda, MD. The action of selected compounds was examined for potential inhibition of tubulin as...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm2012694
更新日期：2012-03-08 00:00:00
abstract：:Herein we describe the development of a focused series of functionalized pyridazin-3(2 H)-one-based formyl peptide receptor (FPR) agonists that demonstrate high potency and biased agonism. The compounds described demonstrated biased activation of prosurvival signaling, ERK1/2 phosphorylation, through diminution of the...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01912
更新日期：2019-05-23 00:00:00
abstract：:The design, synthesis, and activity of a novel series of 2,5-substituted tryptamine derivatives at vascular 5HT1B-like receptors is described. Several important auxiliary binding sites of the 5HT1B-like receptor have been proposed following various modifications to the 2-substituent and especially to the methylene- or...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9605849
更新日期：1997-07-18 00:00:00
abstract：:The C-terminal "address" sequences of prodynorphin-derived opioid peptides contain an unusually high proportion of basic residues, which are known to be crucial for conferring high activity and selectivity for kappa-opioid receptors. In an effort to investigate the possibility that the polycationic "tails" may be invo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00113a020
更新日期：1991-09-01 00:00:00
abstract：:The N-arginyl derivative of methionine-enkephalin (fragment 60-65 of beta-lipotropin) has been shown to be equiactive with the parent pentapeptide, despite the fact that the tyrosine amino group in this compound has been neutralized by the formation of an amide linkage. A series of N-(amino acid) derivatives of (-)-5,...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00143a007
更新日期：1981-11-01 00:00:00
abstract：:To study the influence of substitution of CN for C identical to CH in the anti-herpes virus nucleoside 5-(propynyloxy)-2'-deoxyuridine (1), 5-[(cyanomethylene)oxy]-2'-deoxyuridine (2) was prepared. When the potassium salt of 5-hydroxy-2'-deoxyuridine was reacted with iodoacetonitrile in dry DMF, the bisalkylated produ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00136a007
更新日期：1981-04-01 00:00:00
abstract：:7-(Aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (SK&F 29661, 1) is a potent inhibitor of the enzyme phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28). In contrast to other inhibitors of PNMT, it is also highly selective toward PNMT in comparison with its affinity toward the alpha 2-adrenoceptor (PNMT Ki = 0....
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960235e
更新日期：1997-12-05 00:00:00
abstract：:A one-pot synthesis of ageladine A and analogues is reported. The key Pictet-Spengler reaction between 2-aminohistamine and aryl aldehydes has been successfully utilized for the synthesis of the natural product and 14 analogues. These compounds were screened for their matrix metalloprotease (MMP) and kinase inhibition...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200039m
更新日期：2011-04-14 00:00:00
abstract：:A series of branched-chain sugar isonucleosides was synthesized and evaluated for antiviral activity against herpesviruses. The preparation of homochiral [3S-(3 alpha, 4 beta, 5 alpha)]-2-amino-1, 9-dihydro-9-[tetrahydro-4,5-bis(hydroxymethyl)-3-furanyl]-6H-purin-6-one (7, BMS-181,164) and related compounds was stereo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00061a013
更新日期：1993-04-30 00:00:00
abstract：:A series of highly potent and specific fibrinogen receptor antagonists have been discovered and optimized through structural modification of the novel amidinoindole and benzofuran compounds, I and II. Systematic linker optimization afforded the amidinobenzofuran-containing inhibitor 29, which displayed an IC50 value o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9704863
更新日期：1997-12-19 00:00:00
abstract：:(±)-MRJF22 [(±)-2], a novel prodrug of haloperidol metabolite II (sigma-1 receptor antagonist/sigma-2 receptor agonist ligand) obtained by conjugation to valproic acid (histone deacetylase inhibitor) via an ester bond, exhibits antiangiogenic activity, being able to reduce human retinal endothelial cell (HREC) viabili...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b01039
更新日期：2016-11-10 00:00:00
abstract：:A series of renin inhibitors have been prepared and evaluated for their susceptibility to cleavage by the serine protease chymotrypsin. The compounds were designed by consideration of the structural requirements in the active-site region of renin and chymotrypsin. By systematic alteration of the P3 phenylalanine resid...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00120a006
更新日期：1988-12-01 00:00:00
abstract：:In order to study the preferential involvement of mu or delta receptors in the analgesic effects of enkephalins, several peptides which selectively interact with these two kinds of receptors in peripheral organs were synthesized. The inhibitory potency on the electrically stimulated mouse vas deferens (delta receptors...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00142a002
更新日期：1981-10-01 00:00:00
abstract：:Hydrolysis of the carbamate side chains in phenserine [(-)1] and physostigmine [(-)2] yields the metabolite (-)-eseroline (3), and the red dye rubreserine (4) on air oxidation of the former compound. Both compounds lacked anticholinesterase activity in concentrations up to 30 mM, which would be unachievable in vivo. A...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9800494
更新日期：1998-06-18 00:00:00
abstract：:An endogenous heptadecapeptide, nociceptin/orphanin FQ (N/OFQ), and a G-protein-coupled receptor, N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor], have been described in terms of its structure, distribution, and pharmacology. Thus, the N/OFQ and NOP receptor are located in the central nervous ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm7012979
更新日期：2009-02-12 00:00:00
abstract：:A new goup of acridone derivatives, obtained by reaction of acridone-4-carboxylic acid derivatives with aromatic amines, was tested to determine the inhibitory properties toward the NS3 helicase of hepatitis C virus (HCV). Six compounds inhibited the NS3 helicase at low concentrations (IC(50) from 1.5 to 20 microM). T...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm901741p
更新日期：2010-04-22 00:00:00
abstract：:Conformational restriction of previously disclosed acyclic (diphenylethyl)diphenylacetamides led to the discovery of several potent inhibitors of acyl CoA:cholesterol acyltransferase (ACAT). cis-[2-(4-Hydroxyphenyl)-1-indanyl]diphenylacetamide (4a) was the most potent ACAT inhibitor identified (IC50 = 0.04 microM in a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950833d
更新日期：1996-04-12 00:00:00
