- Selective Fragments for the CREBBP Bromodomain Identified from an Encoded Self-assembly Chemical Library
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DNA-encoded chemical libraries (DECLs) are collections of chemical moieties individually coupled to distinctive DNA barcodes. Compounds can be displayed either at the end of a single DNA strand (i. e., single-pharmacophore libraries) or at the extremities of two complementary DNA strands (i. e., dual-pharmacophore libraries). In this work, we describe the use of a dual-pharmacophore encoded self-assembly chemical (ESAC) library for the affinity maturation of a known 4,5-dihydrobenzodiazepinone ring (THBD) acetyl-lysine (KAc) mimic for the cyclic-AMP response element binding protein (CREB) binding protein (CREBBP or CBP) bromodomain. The new pair of fragments discovered from library selection showed a sub-micromolar affinity for the CREBBP bromodomain in fluorescence polarization and ELISA assays, and selectivity against BRD4(1).
- Catalano, Marco,Moroglu, Mustafa,Balbi, Petra,Mazzieri, Federica,Clayton, James,Andrews, Katrina H.,Bigatti, Martina,Scheuermann, J?rg,Conway, Stuart J.,Neri, Dario
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Read Online
- Rationale design of biotinylated antimalarial endoperoxide carbon centered radical prodrugs for applications in proteomics
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The semisynthetic artemisinin derivatives such as artesunate and artemether, along with the fully synthetic endoperoxide antimalarials (e.g., OZ277, Nature 2004, 430, 900-904), are believed to mediate their antimalarial effects by iron-induced formation of carbon-centered radicals capable of alkylating heme and/or protein. Here, we describe the design and synthesis of a series of biotinylated endoperoxide probe molecules for use in proteomic studies. The target molecules include derivatives of the artemisinin and OZ families, and we demonstrate that these conjugates express nanomolar in vitro activity versus cultured strains of Plasmodium falciparum. We also describe the synthesis of chemically cleavable linked conjugates designed to enable mild elution of labeled proteins during target protein identification.
- Barton, Victoria,Ward, Steven A.,Chadwick, James,Hill, Alasdair,O'Neill, Paul M.
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supporting information; experimental part
p. 4555 - 4559
(2010/08/06)
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- CALCIUM ION CHANNEL MODULATORS and USES THEREOF
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Compounds of formula (I), wherein R1 is hydrogen, hydroxyl or aralkyl; R2 is an optionally substituted alkyl, aryl or heteroaryl (said substituents are selected from hydroxyl, alkoxyl, haloalkoxyl, aryl, heteroaryl, cycloalkyl, amino, monoalkylamino, dialkylamino, alkylsulphonyl, alkylsulphinyl, alkylsulphonylamino, acylamino, saturated or partially unsaturated heterocyclic groups and groups of formula COY); W is selected from oxygen, sulphur, groups of formula NR7, wherein R7 is hydrogen, alkyl, aryl or heteroaryl and groups of formula CR8R9, wherein R8 and R9 are hydrogen, alkyl, aryl or heteroaryl; and X is selected from nitrogen and groups of formula CR10, wherein R10 is hydrogen, alkyl, aryl, heteroaryl, halogen or haloalkyl, inhibit the interaction between Cavx channels and Cavβ proteins and are of use in the treatment and prevention of a number of diseases and conditions including pain and lower urinary tract disorders.
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(2010/04/27)
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- INDOLE- 3 -GLYOXYLAMIDE DERIVATIVES FOR USE AS CALCIUM ION CHANNEL MODULATORS
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Compounds of formula (I) are of use in treating a range of conditions, including pain.
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(2009/12/05)
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- Synthesis and pharmacological studies of new hybrid derivatives of fentanyl active at the μ-opioid receptor and I2-imidazoline binding sites
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Two series of fentanyl-derived hybrid molecules bearing potent I2-imidazoline binding site (IBS) ligands (i.e., guanidine and BU224 moieties) linked with an aliphatic (m = 2, 3, 4, 6, 7, 8, 9 and 12 methylene units) or aromatic spacer were prepared. Their affinities for the μ-opioid receptors and for the I2-IBS were determined through competition binding studies on human postmortem brain membranes. Whereas the BU224 hybrid molecules bound to the μ-opioid receptor and the I2-IBS in the micromolar to low micromolar range, the alkaneguanidine series exhibited remarkable affinities in the nanomolar range for both receptors. [35S]GTPγS functional assays were performed on human postmortem brain membranes with selected ligands from each series (4f and 8g) showing the highest dual affinity for the μ-opioid receptor and I2-IBS affinities. Both compounds displayed agonist properties: at the μ-opioid receptor for the alkaneguanidine derivative 4f (spacer: six methylene units) and at a G-protein coupled receptor (GPCR) which remains to be determined for 8g. The lack of analgesic properties of 4f in vivo (i.e., hot plate and writhing tests in mice), discordant with the good in vitro binding data (Ki μ = 1.04 ± 0.28 nM, Ki I2 = 409 ± 238 nM), may possibly be due to the low intrinsic efficacy of the compound. Alternatively, a low access to the central nervous system for this kind of hybrid molecules cannot be ruled out. Two new compounds reported here (9f and 13), which were not dual acting, are worth mentioning for their outstanding binding affinities; 9f bound to the μ-opioid receptor with a picomolar affinity (Ki = 0.0098 ± 0.0033 nM), whereas 13 presented an I2-IBS affinity (Ki = 18 ± 11 nM) similar to the reference compound BU224.
- Dardonville, Christophe,Fernandez-Fernandez, Cristina,Gibbons, Sarah-Louise,Ryan, Gary J.,Jagerovic, Nadine,Gabilondo, Ane M.,Meana, J. Javier,Callado, Luis F.
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p. 6570 - 6580
(2007/10/03)
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- Pyrimidine derivatives useful as inhibitors of PKC-theta
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Disclosed are novel compounds of formula (I): wherein X, Y, R1, R2 and R3 are as defined herein, which are useful as inhibitors of PKC-theta and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of PKC-theta, including immunological disorders and type II diabetes. This invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
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(2008/06/13)
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- 5-Substituted isoquinoline derivatives
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A compound represented by the following formula (1) or a salt thereof: wherein R1 represents hydrogen atom, a halogen atom and the like; R2 represents hydrogen atom, a halogen atom, a C1-6 alkyl group and the like; and R3 represents —O—X—C(A1)(A11)—C(A2)(A2l)—N(A3l)(A3)(X represents propylene group etc., A11 and A21 represent hydrogen atom, or a C1-6 alkyl group, A31 represents a C1-6 alkyl group substituted with hydroxyl group, or hydrogen atom, and A1, A2, and A3 represent hydrogen atom, a C1-6 alkyl group and the like) and the like, which has an inhibitory activity on the phosphorylation of myosin regulatory light chain, and is useful for treatment of diseases relating to contraction of various cells and the like.
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- PYRROLIDINE DERIVATIVES AS TRYPTASE INHIBITORS
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Compounds of a certain formula 1 in which M, B1, B2, R2, K1 and K2 have the meanings indicated in the description are novel effective tryptase inhibitors.
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(2010/02/06)
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- Unexpected enhancement of thrombin inhibitor potency with o-aminoalkylbenzylamides in the P1 position
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Thrombin inhibitors incorporating o-aminoalkylbenzylamides in the P1 position were designed, synthesized and found to have enhanced potency and selectivity in several different structural classes. X-ray crystallographic analysis of compound 24 bound in the α-thrombin-hirugen complex provides an explanation for these unanticipated results.
- Rittle, Kenneth E.,Barrow, James C.,Cutrona, Kellie J.,Glass, Kristen L.,Krueger, Julie A.,Kuo, Lawrence C.,Lewis, S. Dale,Lucas, Bobby J.,McMasters, Daniel R.,Morrissette, Matthew M.,Nantermet, Philippe G.,Newton, Christina L.,Sanders, William M.,Yan, Youwei,Vacca, Joseph P.,Selnick, Harold G.
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p. 3477 - 3482
(2007/10/03)
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- Synthesis of N-benzyl- and N-phenyl-2-amino-4,5-dihydrothiazoles and thioureas and evaluation as modulators of the isoforms of nitric oxide synthase
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Inhibition of the isoforms of nitric oxide synthase (NOS) has important applications in therapy of several diseases, including cancer. Using 1400W [N-(3-aminomethylbenzyl)acetamidine], thiocitrulline and N δ-(4,5-dihydrothiazol-2-yl)ornithine as lead compounds, series of N-benzyl- and N-phenyl-2-amino-4,5-dihydrothiazoles and thioureas were designed as inhibitors of NOS. Ring-substituted benzyl and phenyl isothiocyanates were synthesised by condensation of the corresponding amines with thiophosgene and addition of ammonia gave the corresponding thioureas in high yields. The substituted 2-amino-4,5-dihydrothiazoles were approached by two routes. Treatment of simple benzylamines with 2-methylthio-4,5-dihydrothiazole at 180 °C afforded the corresponding 2-benzylamino-4,5-dihydrothiazoles. For less nucleophilic amines and those carrying more thermally labile substituents, the 4,5-dihydrothiazoles were approached by acid-catalysed cyclisation of N-(2-hydroxyethyl)thioureas. This cyclisation was shown to proceed by an SN2-like process. Modest inhibitory activity was shown by most of the thioureas and 4,5-dihydrothiazoles, with N-(3-aminomethylphenyl)thiourea (IC50=13 μM vs rat neuronal NOS and IC50=23 μM vs rat inducible NOS) and 2-(3-aminomethylphenylamino)-4,5-dihydrothiazole (IC50=13 μM vs rat neuronal NOS and IC50=19 μM vs human inducible NOS) being the most potent. Several thioureas and 4,5-dihydrothiazoles were found to stimulate the activity of human inducible NOS in a time-dependent manner.
- Goodyer, Claire L. M.,Chinje, Edwin C.,Jaffar, Mohammed,Stratford, Ian J.,Threadgill, Michael D.
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p. 4189 - 4206
(2007/10/03)
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- Synthesis of Macrocyclic, Triazine-Based Receptor Molecules
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The synthesis of triazine-based macrocyclic scaffolds is presented. The strategy employed allows for the facile functionalization of the macrocyclic molecules and combinatorial construction of putative receptor molecules. It is shown that the functional groups on the macrocyclic molecules, the size of the rings and the nature of the diamines linking the triazines can all be varied. In addition to the description of the stepwise synthesis of these compounds, it is shown that macrocycles based on triazine and xylenediamine are able to bind pyranosides and cyanuric acid.
- Loewik, Dennis W. P. M.,Lowe, Christopher R.
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p. 2825 - 2840
(2007/10/03)
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- Substituted urea and isothiourea derivatives as no synthase inhibitors
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PCT No. PCT/GB94/02138 Sec. 371 Date Mar. 28, 1996 Sec. 102(e) Date Mar. 28, 1996 PCT Filed Oct. 3, 1994 PCT Pub. No. WO95/09619 PCT Pub. Date Apr. 13, 1995The use of an N-substituted urea derivative for the manufacture of a medicament for the treatment o
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the Formula IX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- Acetamidine derivatives and their use as inhibitors for the nitric oxide synthase
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A class of acetamidine derivatives of general formula (I) STR1 wherein R1 is hydrogen, C1-6 hydrocarbyl group optionally substituted by halo, halo, nitro, cyano or a group XR3 wherein X is oxygen, C(O)m wherein m is 1 or 2, S(O)n wherein n is 0, 1 or 2, or a group NR4 wherein R4 is hydrogen or C1-6 alkyl; and R3 is hydrogen, C1-6 alkyl, or a group NR5 R6 wherein R5 and R6 are independently hydrogen or C1-6 alkyl, provided that R3 is not NR5 R6 when X is oxygen or S(O)n; R1a and R1b are independently selected from hydrogen and halo; R2 is a C1-14 hydrocarbyl group which may optionally contain one or two heteroatoms, the group R2 being optionally substituted by one or more groups independently selected from halo; N3 ; nitro; CF3 ; ZR7 wherein Z is oxygen, C(O)m' wherein m' is 1 or 2, S(O)n' wherein n' is 0, 1 or 2, or a group NR8 wherein R8 is hydrogen or C1-6 alkyl and R7 is hydrogen, C1-6 alkyl or a group NR9 R10 wherein R9 and R10 are independently hydrogen or C1-6 alkyl; or R2 is substituted by a group (a) STR2 wherein R11 has a definition the same as for R1 ; with the proviso that when R1 is a C1-6 alkyl group and R2 is a C1-14 hydrocarbyl substituted by two groups ZR7 wherein one group ZR7 is CO2 H, the other group ZR7 is not NH2; and salts thereof, methods for the manufacture thereof, and therapies, particularly inhibtion of nitric oxide synthase, is disclosed.
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the FormulaIX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the FormulaIX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the FormulaIX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the FormulaIX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- Arylsulfonylaminobenzene derivatives and the use thereof as factor Xa inhibitors
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The present invention is directed to non-peptidic factor Xa inhibitors which are useful for the treatment of arterial and venous thrombotic occlusive disorders, inflammation, cancer, and neurodegenerative diseases. The factor Xa inhibitors provide compounds of structure: STR1 or pharmaceutically acceptable salts thereof; wherein R1 is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; R2 is one of hydrogen, alkyl, cycloalkyl or aryl; R3 is one of hydrogen, hydroxy or alkoxy; R4 is one of --NH2, phenyl or pyridyl, wherein said phenyl and said pyridyl are optionally substituted with one or two of halogen, hydroxy, hydroxyalkyl, alkoxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl and/or dialkylaminoalkyl; X is one of --CH2 -- or --C(O)--; and n is from zero to eleven; provided that when R4 is --NH2, then R3 is hydrogen and n is other than zero; and also provided that when R3 is hydroxy or alkoxy, then R4 is other than --NH2, and n is other than zero.
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- Solid and Solution Phase Organic Syntheses of Oligomeric Thioureas
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In order to study supramolecular architectures built from unnatural oligomeric and polymeric structures, one must first have an efficient synthetic strategy to produce them. Oligomers built from thiourea groups should form complex secondary and tertiary structures due to the hydrogenbonding capabilities of the thioureas. Herein, both solution and solid phase synthetic procedures that yield oligomeric thioureas are described. They rely on the coupling of an isothiocyanate with an amine to produce the thiourea linkage. The monomers are derived from simple diamines. Higher yields are achieved using the solid phase method due to the ability to easily monitor the extent of reaction, to use a large excess of reagent, and to perform purification after cleavage from the solid support. A variety of oligomers are given as examples. The procedure is quite general, should be easily extended to complex monomers, and will allow the investigation of intramolecular and intermolecular interactions.
- Smith, Joseph,Liras, Jennifer L.,Schneider, Stephen E.,Anslyn, Eric V.
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p. 8811 - 8818
(2007/10/03)
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- Acceleration of Substitution Reactions of a Phosphoric Acid Diester by Bis(guanidinium) Compounds
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Ion-pair coordination of phosphoric acid diesters with positively charged guanidines may cause large rate accelerations in substitution reactions.Here we present a comparative study on the catalytical influence of several mono- bis- and tris(guanidines) a
- Gross, Ralf,Duerner, Gerd,Goebel, Michael W.
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- Structure-activity relationships of novel vasopressin antagonists containing C-terminal diaminoalkanes and (aminoalkyl)guanidines
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We report the synthesis and biological activity of a series of analogues of the vasopressin antagonists [Pmp1,D-Tyr(Et)2,Val4]arginine-vasopressin (1) and [Pmp1,D-Tyr(Et)2,Val4,desGly9]arginine-vasopressin (2), where part or all of the tripeptide tail has been replaced by a simple alkyldiamine [NH(CH2)(n)NH2] or (aminoalkyl)guanidine [NH(CH2)(n)NHC(=NH)NH2] in order to examine the effects that variation of the length and orientation of the tripeptide tail have on renal vasopressin (V2) receptor antagonist activity. The results show that the entire tripeptide tail (Pro-Arg-Gly-NH2) can be replaced by an alkyldiamine or an (aminoalkyl)guanidine, compounds 15 and 16, respectively, indicating that there is no orientational requirement for the basic functional group coming off the cyclic hexapeptide ring. Also, there seems to be an 'optimal' distance between the basic functional group and the hexapeptide ring since receptor affinity of the antagonists begins to fall off when the basic functional group is too close (compound 13) or extends too far (compounds 8-10) from the hexapeptide ring. These results suggest all that is necessary for retention of antagonist affinity and potency is a basic functional group, amine or guanidine, extended an optimal distance from the hexapeptide ring.
- Callahan,Ashton-Shue,Bryan,Bryan,Heckman,Kinter,McDonald,Moore,Schmidt,Silvestri,Stassen,Sulat,Yim,Huffman
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p. 391 - 396
(2007/10/02)
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