108467-99-8Relevant articles and documents
Selective Fragments for the CREBBP Bromodomain Identified from an Encoded Self-assembly Chemical Library
Catalano, Marco,Moroglu, Mustafa,Balbi, Petra,Mazzieri, Federica,Clayton, James,Andrews, Katrina H.,Bigatti, Martina,Scheuermann, J?rg,Conway, Stuart J.,Neri, Dario
, p. 1752 - 1756 (2020)
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).
CALCIUM ION CHANNEL MODULATORS and USES THEREOF
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Page/Page column 103, (2010/04/27)
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.
Synthesis and pharmacological studies of new hybrid derivatives of fentanyl active at the μ-opioid receptor and I2-imidazoline binding sites
Dardonville, Christophe,Fernandez-Fernandez, Cristina,Gibbons, Sarah-Louise,Ryan, Gary J.,Jagerovic, Nadine,Gabilondo, Ane M.,Meana, J. Javier,Callado, Luis F.
, p. 6570 - 6580 (2007/10/03)
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.
