Abstract:
:Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid aldose reductase inhibitors. The lead candidate, 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat, 9) inhibits aldose reductase with an IC(50) of 5 nM, while being 5400 times less active against aldehyde reductase, a related enzyme involved in the detoxification of reactive aldehydes. It lowers nerve and lens sorbitol levels with ED(50)'s of 1.9 and 4.5 mg/kg/d po, respectively, in the 5-day STZ-induced diabetic rat model. In a 3-month diabetic intervention model (1 month of diabetes followed by 2 months of drug treatment at 5 mg/kg/d po), it normalizes polyols and reduces the motor nerve conduction velocity deficit by 59% relative to diabetic controls. It has a favorable pharmacokinetic profile (F, 82%; t(1/2), 5.6 h; Vd, 0.694 L/kg) with good drug penetration in target tissues (C(max) in sciatic nerve and eye are 2.36 and 1.45 mug equiv/g, respectively, when dosed with [(14)C]lidorestat at 10 mg/kg po).
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Van Zandt MC,Jones ML,Gunn DE,Geraci LS,Jones JH,Sawicki DR,Sredy J,Jacot JL,Dicioccio AT,Petrova T,Mitschler A,Podjarny ADdoi
10.1021/jm0492094keywords:
subject
Has Abstractpub_date
2005-05-05 00:00:00pages
3141-52issue
9eissn
0022-2623issn
1520-4804journal_volume
48pub_type
杂志文章abstract::This work reports on the synthesis, characterization, and in vitro cytotoxic activity of some new platinum(II), palladium(II), and gold(III) derivatives of methylsarcosinedithiocarbamate and its S-methyl ester, to study their behavior as potential antitumor agents. The biological activity of these compounds, as determ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049191x
更新日期:2005-03-10 00:00:00
abstract::Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation cascade. To investigate the potential of FXIa inhibitors as safe anticoagulants, a series of potent, selectiv...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm060978s
更新日期:2006-12-28 00:00:00
abstract::To produce reliable predictions of bioactive conformations is a major challenge in the field of structure-based inhibitor design and is a requirement for accurate binding free energy predictions with structure-based methods. A series of HIV-1 reverse transcriptase inhibitors was cross-docked using a non-native crystal...
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doi:10.1021/jm701218j
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abstract::Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in th...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b01088
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abstract::1-Aroylindoline, 1-aroyl-1,2,3,4-tetrahydroquinoline, and 1-aroylindole derivatives were synthesized and evaluated for anticancer activity. The 4-amino and 4-hydroxy-1-aroylindoles 26 and 27 with IC 50 of 0.9 and 0.6 microM, respectively, exhibited antitubulin activity superior or comparable to that of colchicine and ...
journal_title:Journal of medicinal chemistry
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abstract::As a receptor tyrosine kinase of insulin receptor (IR) subfamily, anaplastic lymphoma kinase (ALK) has been validated to play important roles in various cancers, especially anaplastic large cell lymphoma (ALCL), nonsmall cell lung cancer (NSCLC), and neuroblastomas. Currently, five small-molecule inhibitors of ALK, in...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.9b00446
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abstract::Targeting KRAS-PDEδ protein-protein interactions with small molecules represents a promising opportunity for developing novel antitumor agents. However, current KRAS-PDEδ inhibitors are limited by poor cellular antitumor potency and the druggability of the target remains to be validated by new inhibitors. To tackle th...
journal_title:Journal of medicinal chemistry
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abstract::A series of 3-imino-2-indolones are the first published, high-affinity antagonists of the galanin GAL3 receptor. One example, 1,3-dihydro-1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (9), was shown to have high affinity for the human GAL3 receptor (Ki=17 nM) and to be highly selective for GAL3 over a b...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm060001n
更新日期:2006-06-29 00:00:00
abstract::Some 2-aryloxymethyl-2,3,5,6-tetrahydro-1,4-oxazines have been shown to possess marked antidepressant activity. The 1,4-oxazines were synthesized by lithium aluminum hydride reduction of the readily available 6-aryloxymethyl-2,3,5,6-tetrahydro-1,4-oxazin-3-ones. High antidepressant activity was associated with ortho s...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00240a009
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abstract::A series of cyclic pseudopeptides of the formula cyclo(Leu psi[CH2NH]Xaa-Gln-Trp-Phe-beta Ala), where Xaa represents the residue of an alpha-amino acid, has been synthesized in order to establish the role of the Xaa side chain for tachykinin NK-2 receptor antagonist activity. Syntheses have been carried out in solid p...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00047a020
更新日期:1994-10-14 00:00:00
abstract::A series of hexadeoxyribonucleotides (6-mers), d(TGGGAG), substituted with a variety of aromatic groups at the 5'-end were synthesized and tested for anti-human immunodeficiency virus type 1 (HIV-1) activity. While unmodified d(TGGGAG) (31) had no anti-HIV-1 activity, compound 23 with a 3,4-di(benzyloxy)benzyl (DBB) g...
journal_title:Journal of medicinal chemistry
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doi:10.1021/jm970658w
更新日期:1998-09-10 00:00:00
abstract::Reformatski condensation of benzyl 2-bromopropionate with 4-carbomethoxybenzaldehyde, followed by dehydration afforded benzyl 2-methyl-p-carbomethoxycinnamate (4a). Hydrogenation over a Pd catalyst gave the hydrocinnamic acid 5a. Conversion to the chloromethyl (6a) and azidomethyl ketone (7a) was followed by hydrogena...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00163a035
更新日期:1990-01-01 00:00:00
abstract::The need for drugs that lack the obtrusive and limiting side effects of the tricyclic antidepressants has prompted the search for agents with greatly enhanced selectivity for specific mechanisms believed to be essential for antidepressant efficacy. The potential role of derangements of 5-HT pathways in the etiology of...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00377a021
更新日期:1984-11-01 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-activity relationship studies of substituted arylsulfoanilides as antiproliferatives, which are mediated by the partial depletion of intracellular Ca(2+) stores, resulted in the identification of compounds with micromolar activity against lung cancer cells in a growth inhibition assay. Incorporating the subs...
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doi:10.1021/jm0496234
更新日期:2004-10-07 00:00:00
abstract::Chemical probes of microRNA (miRNA) function are potential tools for understanding miRNA biology that also provide new approaches for discovering therapeutics for miRNA-associated diseases. MicroRNA-21 (miR-21) is an oncogenic miRNA that is overexpressed in most cancers and has been strongly associated with driving ch...
journal_title:Journal of medicinal chemistry
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doi:10.1021/acs.jmedchem.7b01891
更新日期:2018-07-26 00:00:00
abstract::To eliminate an unwarranted metabolic pathway of the quinoline ring, a set of two compounds, where C-2 position of the antimalarial drug primaquine is blocked by metabolically stable bulky alkyl group are synthesized. Compound 2 [R = C(CH(3))(3)] of the series has produced excellent antimalarial efficacy against P. be...
journal_title:Journal of medicinal chemistry
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doi:10.1021/jm0304562
更新日期:2004-01-15 00:00:00
abstract::Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA(4)H) as a key target for the treatment of cardiovascular disease. We combined fragment-based crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA(4)H. Lig...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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abstract::In this study, we developed an assignment-free approach for rapid identification of ligand-binding sites in target proteins by using NMR. With a sophisticated cell-free stable isotope-labeling procedure that introduces (15)N- or (13)C-labels to specific atoms of target proteins, this approach requires only a single se...
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abstract::The alpha- and beta-D-lyxofuranosyl analogues of the naturally occurring nucleosides have been synthesized and their antiviral properties examined. The alpha anomers were prepared by glycosylation of purine and pyrimidine aglycons with tetra-O-acetyl-alpha-D-lyxofuranose, followed by removal of the blocking groups. Th...
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abstract::The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC(50) = 6.1 ± 1.0 nM) from in-house screening. Detailed structure-activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallo...
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abstract::A novel series of C-3 substituted 4,6-dichloroindole-2-carboxylic acids was synthesized to investigate the influence of different hydrogen-bond donor and acceptor groups at this specific position on the affinity to the glycine site of the NMDA receptor. These novel 3-indolylmethyl derivatives with ring-open (amines, s...
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更新日期:2003-01-02 00:00:00
abstract::10-Acetyl-7,8-dihydroxyxantho[2,3-f]tetralin is obtained by photo-Fries rearrangement of an acylated and double ketal protected tetralin followed by sodium thiocresylate catalyzed rearrangement of the resulting benzoyltetralin. Introduction of the 10-hydroxy function with base, triethyl phosphite, and molecular oxygen...
journal_title:Journal of medicinal chemistry
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更新日期:2011-05-12 00:00:00
abstract::5-Bromotryptophan (5-BrTrp) is the most potent amino acid derivative reported in the literature to inhibit the gelation of hemoglobin S (from sickle cell anemia patients). Trp-Trp is also more potent than Trp as an antigelation agent. Therefore, we have prepared a series of dipeptides containing 5-BrTrp and evaluated ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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更新日期:1990-12-01 00:00:00
abstract::The design and synthesis of potent and selective neurokinin NK-2 receptor agonists 12 (GR64349) and 31 are described, together with structure-activity relationships for related analogues. Compound 12 (EC50 = 3.7 nM at NK-2 receptors in the rat colon; selectivity > 1000- and > 300-fold with respect to NK-1 and NK-3 rec...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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abstract::Four nucleoside analogues ( 1- 4) containing a common heterocyclic base, 4(7)-amino-6(5) H-imidazo[4,5- d]pyridazin-7(4)one, were screened against calf-intestine adenosine deaminase. Compounds 1 and 3 with K(i) values of 10-12 microM are more than four times as potent inhibitors of ADA compared with 2 and 4, with K(i)...
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