Investigations into the origin of the molecular recognition of several adenosine deaminase inhibitors.

Abstract:

:Inhibitors of adenosine deaminase (ADA, EC 3.5.4.4) are potential therapeutic agents for the treatment of various health disorders. Several highly potent inhibitors were previously identified, yet they exhibit unacceptable toxicities. We performed a SAR study involving a series of C2 or C8 substituted purine-riboside analogues with a view to discover less potent inhibitors with a lesser toxicity. We found that any substitution at C8 position of nebularine resulted in total loss of activity toward calf intestinal ADA. However, several 2-substituted-adenosine, 8-aza-adenosine, and nebularine analogues exhibited inhibitory activity. Specifically, 2-Cl-purine riboside, 8-aza-2-thiohexyl adenosine, 2-thiohexyl adenosine, and 2-MeS-purine riboside were found to be competitive inhibitors of ADA with K(i) values of 25, 22, 6, and 3 μM, respectively. We concluded that electronic parameters are not major recognition determinants of ADA but rather steric parameters. A C2 substituent which fits ADA hydrophobic pocket and improves H-bonding with the enzyme makes a good inhibitor. In addition, a gg rotamer about C4'-C5' bond is apparently an important recognition determinant.

journal_name

J Med Chem

authors

Gillerman I,Fischer B

doi

10.1021/jm101286g

subject

Has Abstract

pub_date

2011-01-13 00:00:00

pages

107-21

issue

1

eissn

0022-2623

issn

1520-4804

journal_volume

54

pub_type

杂志文章
  • Antiinflammatory activity of some 2,3-dihydrobenzofuran-5-acetic acids and related compounds.

    abstract::A series of 2,3-dihydrobenzofuran-5-acetic acids and related compounds was prepared as potential antiinflammatory agents. As measured by the carrageenan-induced edema method for the preliminary screening test, introduction of a methyl group alpha to the acetic acid function enhanced the antiinflammatory activity, and ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00224a020

    authors: Hirose N,Kuriyama S,Kato Y,Toyoshima S

    更新日期:1976-02-01 00:00:00

  • Latent alkyl isocyanates as inhibitors of aldehyde dehydrogenase in vivo.

    abstract::On the basis of our previous observation that N1-alkyl substituted chlorpropamide derivatives when administered to rats nonenzymatically eliminated n-propyl isocyanate, a known inhibitor of aldehyde dehydrogenase (AlDH), we have synthesized other latentiated n-propyl isocyanates as in vivo inhibitors of AlDH. N1-Allyl...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00050a018

    authors: Nagasawa HT,Elberling JA,Goon DJ,Shirota FN

    更新日期:1994-11-25 00:00:00

  • Cardiotonic agents. 5. 1,2-Dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3- pyridinecarbonitriles and related compounds. Synthesis and inotropic activity.

    abstract::Several 1,2-dihydro-5-(substituted phenyl)-2(1H)-pyridinones were synthesized and evaluated for inotropic activity. 1,2-Dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3- pyridinecarbonitrile (5a) and the corresponding unsubstituted analogue 14a were the most potent positive inotropic agents in this series. Alth...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00389a011

    authors: Sircar I,Duell BL,Bristol JA,Weishaar RE,Evans DB

    更新日期:1987-06-01 00:00:00

  • Discovery of 5-substituted-6-chlorouracils as efficient inhibitors of human thymidine phosphorylase.

    abstract::Thymidine phosphorylase plays an important role in angiogenesis, which is an attractive target for therapy of cancer and other diseases. In our continuous effort to develop novel inhibitors of thymidine phosphorylase, we have discovered that 6-halouracils substituted at position C5 by certain hydrophobic groups exhibi...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm070644i

    authors: Nencka R,Votruba I,Hrebabecký H,Jansa P,Tloust'ová E,Horská K,Masojídková M,Holý A

    更新日期:2007-11-29 00:00:00

  • Synthesis and antimicrobial activity of 4H-4-oxoquinolizine derivatives: consequences of structural modification at the C-8 position.

    abstract::The antibacterial 4H-4-oxoquinolizines were introduced recently to overcome bacterial resistance to fluoroquinolones. They exhibit potent antibacterial activity against Gram-positive, Gram-negative, and anaerobic organisms and are highly active against some quinolone-resistant bacteria including quinolone-resistant MR...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm990191k

    authors: Ma Z,Chu DT,Cooper CS,Li Q,Fung AK,Wang S,Shen LL,Flamm RK,Nilius AM,Alder JD,Meulbroek JA,Or YS

    更新日期:1999-10-07 00:00:00

  • Structure-activity relationships of kadsurenone analogues.

    abstract::Kadsurenone, a specific receptor antagonist of platelet-activating factor (PAF), and its analogues were prepared from derivatives of cinnamyl alcohol and (allyloxy)phenol. Racemic kadsurenone, resolvable by a Chiralpak column at low temperatures, has an IC50 value of 2 X 10(-7) M, which is about 50% of the activity of...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00384a023

    authors: Ponpipom MM,Bugianesi RL,Brooker DR,Yue BZ,Hwang SB,Shen TY

    更新日期:1987-01-01 00:00:00

  • Design, Synthesis, and Activity Study of Water-Soluble, Rapid-Release Propofol Prodrugs.

    abstract::In this work, a series of water-soluble propofol prodrugs were synthesized, and their propofol release rate and pharmacodynamic characteristics were measured. We found that inserting glycolic acid as a linker between propofol and the cyclic amino acid accelerated the release of propofol from prodrugs into the plasma w...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/acs.jmedchem.0c00698

    authors: Liu LQ,Hong PX,Song XH,Zhou CC,Ling R,Kang Y,Qi QR,Yang J

    更新日期:2020-07-23 00:00:00

  • Mineralocorticoid properties of potential metabolites of 18-hydroxydeoxycorticosterone and 18-hydroxyprogesterone.

    abstract::The high secretion rate of 18-hydroxydeoxycorticosterone in hypertensives and the steroids implication as a mineralocorticoid has led to the synthesis of potential di-, tetra-, and hexahydro metabolites of it and 18-hydroxy-progesterone. These potential metabolites have been synthesized by reduction of the double bond...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00380a014

    authors: Weet JF,Lenz GR

    更新日期:1985-02-01 00:00:00

  • Synthesis of N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid as dual inhibitors of dihydrofol

    abstract::Two novel classical antifolates N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid 3 and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid 4 were designed, synthesized, and evaluated as antitumor agents. Compounds ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm058234m

    authors: Gangjee A,Lin X,Kisliuk RL,McGuire JJ

    更新日期:2005-11-17 00:00:00

  • Design, synthesis, and structure--activity relationship studies for a new imidazole series of J774 macrophage specific acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors.

    abstract::Acyl-CoA:cholesterol acyltransferase (ACAT) is the primary enzyme involved in intracellular cholesterol esterification. Arterial wall infiltration by macrophages and subsequent uncontrolled esterification of cholesterol leading to foam cell formation is believed to be an important process which leads to the developmen...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00007a004

    authors: Maduskuie TP Jr,Wilde RG,Billheimer JT,Cromley DA,Germain S,Gillies PJ,Higley CA,Johnson AL,Pennev P,Shimshick EJ

    更新日期:1995-03-31 00:00:00

  • Synthesis and antiviral activity of novel N-substituted derivatives of acyclovir.

    abstract::Novel N-substituted derivatives of acyclovir (1a) were synthesized and evaluated for their antiviral, antimetabolic, and antitumor cell properties in vitro. Monomethylation of 1a at positions 1, 7, and N-2 gave compounds 2-4, respectively. When positions 1 and N-2 were linked together by an isopropeno group, the tricy...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00402a017

    authors: Boryski J,Golankiewicz B,De Clercq E

    更新日期:1988-07-01 00:00:00

  • Synthesis, ex vivo evaluation, and radiolabeling of potent 1,5-diphenylpyrrolidin-2-one cannabinoid subtype-1 receptor ligands as candidates for in vivo imaging.

    abstract::We have reported that [methyl- (11)C] (3 R,5 R)-5-(3-methoxyphenyl)-3-[(R)-1-phenylethylamino]-1-(4-trifluoromethylphenyl)pyrrolidin-2-one ([(11)C] 8, [(11)C]MePPEP) binds with high selectivity to cannabinoid type-1 (CB 1) receptors in monkey brain in vivo. We now describe the synthesis of 8 and four analogues, namely...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm800416m

    authors: Donohue SR,Krushinski JH,Pike VW,Chernet E,Phebus L,Chesterfield AK,Felder CC,Halldin C,Schaus JM

    更新日期:2008-09-25 00:00:00

  • The discovery of I-BET726 (GSK1324726A), a potent tetrahydroquinoline ApoA1 up-regulator and selective BET bromodomain inhibitor.

    abstract::Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflamm...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm5010539

    authors: Gosmini R,Nguyen VL,Toum J,Simon C,Brusq JM,Krysa G,Mirguet O,Riou-Eymard AM,Boursier EV,Trottet L,Bamborough P,Clark H,Chung CW,Cutler L,Demont EH,Kaur R,Lewis AJ,Schilling MB,Soden PE,Taylor S,Walker AL,Walker

    更新日期:2014-10-09 00:00:00

  • General pseudoreceptor model for sweet compounds: a semiquantitative prediction of binding affinity for sweet-tasting molecules.

    abstract::The chemical structures of sweet compounds are very different, ranging from sugars to amino acids and peptides or other compounds such as saccharin. The biological mechanism underlying the generation of sweet taste is still unknown, although in the past few years much research has provided evidence for the existence o...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm020833v

    authors: Bassoli A,Drew MG,Merlini L,Morini G

    更新日期:2002-09-26 00:00:00

  • Potent inhibition of Grb2 SH2 domain binding by non-phosphate-containing ligands.

    abstract::Development of Grb2 Src homology 2 (SH2) domain binding inhibitors has important implications for treatment of a variety of diseases, including several cancers. In cellular studies, inhibitors of Grb2 SH2 domain binding have to date been large, highly charged peptides which relied on special transport devices for cell...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm980388x

    authors: Yao ZJ,King CR,Cao T,Kelley J,Milne GW,Voigt JH,Burke TR Jr

    更新日期:1999-01-14 00:00:00

  • Use of simple docking methods to screen a virtual library for heteroactivators of cytochrome P450 2C9.

    abstract::Several laboratories have demonstrated that activation of drug metabolism by P450s may occur via a mechanism that resembles allosterism from an enzyme kinetic standpoint. Because the effector drug binding site may be located in the same P450 binding pocket where the drug substrate is located, the ability to find and c...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm060706p

    authors: Locuson CW,Gannett PM,Ayscue R,Tracy TS

    更新日期:2007-03-22 00:00:00

  • Synthesis and anticonvulsant activity of N-benzylpyrrolo[2,3-d]-, -pyrazolo[3,4-d]-, and -triazolo[4,5-d]pyrimidines: imidazole ring-modified analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine.

    abstract::Analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine (1) containing isosteric replacements of the imidazole ring atoms were synthesized and tested for anticonvulsant activity. The pyrrolo[2,3-d]-, pyrazolo[3,4-d]-, and triazolo[4,5-d]pyrimidines were less active than 1 against maximal electroshock-induced seizure...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00019a019

    authors: Kelley JL,Davis RG,McLean EW,Glen RC,Soroko FE,Cooper BR

    更新日期:1995-09-15 00:00:00

  • Biological diversity from a structurally diverse library: systematically scanning conformational space using a pyranose scaffold.

    abstract::Success in discovering bioactive peptide mimetics is often limited by the difficulties in correctly transposing known binding elements of the active peptide onto a small and metabolically more stable scaffold while maintaining bioactivity. Here we describe a scanning approach using a library of pyranose-based peptidom...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm1002777

    authors: Abbenante G,Becker B,Blanc S,Clark C,Condie G,Fraser G,Grathwohl M,Halliday J,Henderson S,Lam A,Liu L,Mann M,Muldoon C,Pearson A,Premraj R,Ramsdale T,Rossetti T,Schafer K,Le Thanh G,Tometzki G,Vari F,Verquin G,

    更新日期:2010-08-12 00:00:00

  • Design, synthesis, and evaluation of N-acyl modified sialic acids as inhibitors of adenoviruses causing epidemic keratoconjunctivitis.

    abstract::The adenovirus serotype Ad37 binds to and infects human corneal epithelial (HCE) cells through attachment to cellular glycoproteins carrying terminal sialic acids. By use of the crystallographic structure of the sialic acid-interacting domain of the Ad37 fiber protein in complex with sialyllactose, a set of N-acyl mod...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm801609s

    authors: Johansson S,Nilsson E,Qian W,Guilligay D,Crepin T,Cusack S,Arnberg N,Elofsson M

    更新日期:2009-06-25 00:00:00

  • Design of substrate-based inhibitors of human beta-secretase.

    abstract::By use of the effectively cleaved beta-secretase (BACE) substrate (1), incorporation of a statine in P(1) resulted in a weak inhibitor 13 of the enzyme. Further substitution of P(1)'-Asp by P(1)'-Val in 13 results in a potent inhibitor 22 of BACE. Removal of the P(10)-P(5) residues on the N-terminal part of inhibitor ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm0155695

    authors: Tung JS,Davis DL,Anderson JP,Walker DE,Mamo S,Jewett N,Hom RK,Sinha S,Thorsett ED,John V

    更新日期:2002-01-17 00:00:00

  • Antimalarial phenanthrene amino alcohols. 3. Halogen-containing 9-phenanthrenemethanols.

    abstract::A series of new 9-phenanthrene amino alcohols has been prepared in which each compound bears from one to five halogen or halogen-containing moieties. A number of these compounds are extremely active against Plasmodium berghei in the mouse. Some structural requirements for optimal efficacy are considered. ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00244a012

    authors: Nodiff EA,Saggiomo AJ,Tanabe K,Chen EH,Shinbo M,Tyagi MP,Kozuka A,Otomasu H,Verma BL,Goff D

    更新日期:1975-10-01 00:00:00

  • Fatty acid amide hydrolase inhibitors from virtual screening of the endocannabinoid system.

    abstract::The endocannabinoid system consists of two cannabinoid receptors (CB1 and CB2), endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of the endocannabinoids, including fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL). In the present study, virtual screening of MGL inhibitor...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm060394q

    authors: Saario SM,Poso A,Juvonen RO,Järvinen T,Salo-Ahen OM

    更新日期:2006-07-27 00:00:00

  • Nonlinear quantitative structure-activity relationship for the inhibition of dihydrofolate reductase by pyrimidines.

    abstract::A novel method for quantitative structure-activity relationship (QSAR) analysis is presented. The method, which does not assume any particular functional form for the QSAR, develops nonlinear relationships between parameters describing a set of molecules and the activity of the molecules. For the QSAR of the inhibitio...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm960197z

    authors: Hirst JD

    更新日期:1996-08-30 00:00:00

  • Adenosine kinase inhibitors. 6. Synthesis, water solubility, and antinociceptive activity of 5-phenyl-7-(5-deoxy-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidines substituted at C4 with glycinamides and related compounds.

    abstract::4-(Phenylamino)-5-phenyl-7-(5-deoxy-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine 1 and related compounds known as "diaryltubercidin" analogues are potent inhibitors of adenosine kinase (AK) and are orally active in animal models of pain such as the rat formalin paw model (GP3269 ED50= 6.4 mg/kg). However, the utility...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm050394a

    authors: Bookser BC,Ugarkar BG,Matelich MC,Lemus RH,Allan M,Tsuchiya M,Nakane M,Nagahisa A,Wiesner JB,Erion MD

    更新日期:2005-12-01 00:00:00

  • Synthesis and antitumor activities of novel pyrimidine derivatives of 2,3-O,O-dibenzyl-6-deoxy-L-ascorbic acid and 4,5-didehydro-5,6- dideoxy-L-ascorbic acid.

    abstract::The new pyrimidine derivatives of 2,3-O, O-dibenzyl-6-deoxy-L-ascorbic acid (8-10) were synthesized by condensation of uracil and its 5-fluoro- and 5-trifluoromethyl-substituted derivatives with 4-(5,6-epoxypropyl)-2, 3-O,O-dibenzyl-L-ascorbic acid (7), while pyrimidine derivatives of 4,5-didehydro-5,6-dideoxy-L-ascor...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm0009540

    authors: Raić-Malić S,Svedruzić D,Gazivoda T,Marunović A,Hergold-Brundić A,Nagl A,Balzarini J,De Clercq E,Mintas M

    更新日期:2000-12-14 00:00:00

  • Structure-guided design of selective inhibitors of neuronal nitric oxide synthase.

    abstract::Nitric oxide synthases (NOSs) comprise three closely related isoforms that catalyze the oxidation of L-arginine to L-citrulline and the important second messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal NOS (nNOS) has the potential to be therapeutically beneficial in various neurodegenerati...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm4000984

    authors: Huang H,Li H,Martásek P,Roman LJ,Poulos TL,Silverman RB

    更新日期:2013-04-11 00:00:00

  • Synthesis and antiprotozoal activity of cationic 1,4-diphenyl-1H-1,2,3-triazoles.

    abstract::Novel dicationic triazoles 1-60 were synthesized by the Pinner method from the corresponding dinitriles, prepared via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The type and the placement of cationic moieties as well as the nature of aromatic substituents influenced in vitro antiprotozoal activities o...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm901178d

    authors: Bakunov SA,Bakunova SM,Wenzler T,Ghebru M,Werbovetz KA,Brun R,Tidwell RR

    更新日期:2010-01-14 00:00:00

  • Binding structures and potencies of oxidosqualene cyclase inhibitors with the homologous squalene-hopene cyclase.

    abstract::The binding structures of 11 human oxidosqualene cyclase inhibitors designed as cholesterol-lowering agents were determined for the squalene-hopene cyclase from Alicyclobacillus acidocaldarius, which is the only structurally known homologue of the human enzyme. The complexes were produced by cocrystallization, and the...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm0211218

    authors: Lenhart A,Reinert DJ,Aebi JD,Dehmlow H,Morand OH,Schulz GE

    更新日期:2003-05-22 00:00:00

  • Steroidal alpha-methylene delta-lactones as potential antitumor agents.

    abstract::Four novel steroidal alpha-methylene delta-lactones have been synthesized and shown to be active against human nasopharyngeal carcinoma (KB) cells in culture. The syntheses involved the use of known alpha-methylenation procedures. In addition, the lactone 6 was directly methylenated by reaction with CH2O/KOH or Et2NH/...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00175a019

    authors: Dehal SS,Marples BA,Stretton RJ,Traynor JR

    更新日期:1980-01-01 00:00:00

  • Review of Transient Receptor Potential Canonical (TRPC5) Channel Modulators and Diseases.

    abstract::Transient receptor potential canonical (TRPC) channels are highly homologous, nonselective cation channels that form many homo- and heterotetrameric channels. These channels are highly abundant in the brain and kidney and have been implicated in numerous diseases, such as depression, addiction, and chronic kidney dise...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.1021/acs.jmedchem.8b01954

    authors: Sharma S,Hopkins CR

    更新日期:2019-09-12 00:00:00