- Identification of a novel ligand for the ATAD2 bromodomain with selectivity over BRD4 through a fragment growing approach
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ATAD2 is an ATPase that is overexpressed in a variety of cancers and associated with a poor patient prognosis. This protein has been suggested to function as a cofactor for a range of transcription factors, including the proto-oncogene MYC and the androgen receptor. ATAD2 comprises an ATPase domain, implicated in chromatin remodelling, and a bromodomain which allows it to interact with acetylated histone tails. Dissection of the functional roles of these two domains would benefit from the availability of selective, cell-permeable pharmacological probes. An in silico evaluation of the 3D structures of various bromodomains suggested that developing small molecule ligands for the bromodomain of ATAD2 is likely to be challenging, although recent reports have shown that ATAD2 bromodomain ligands can be identified. We report a structure-guided fragment-based approach to identify lead compounds for ATAD2 bromodomain inhibitor development. Our findings indicate that the ATAD2 bromodomain can accommodate fragment hits (Mr 200) that yield productive structure-activity relationships, and structure-guided design enabled the introduction of selectivity over BRD4.
- Miller, Duncan C.,Martin, Mathew P.,Adhikari, Santosh,Brennan, Alfie,Endicott, Jane A.,Golding, Bernard T.,Hardcastle, Ian R.,Heptinstall, Amy,Hobson, Stephen,Jennings, Claire,Molyneux, Lauren,Ng, Yvonne,Wedge, Stephen R.,Noble, Martin E. M.,Cano, Celine
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Read Online
- Selective Palladium(II)-Catalyzed Carbonylation of Methylene β-C?H Bonds in Aliphatic Amines
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Palladium(II)-catalyzed C?H carbonylation reactions of methylene C?H bonds in secondary aliphatic amines lead to the formation of trans-disubstituted β-lactams in excellent yields and selectivities. The generality of the C?H carbonylation process is aided by the action of xantphos-based ligands and is important in securing good yields for the β-lactam products.
- Cabrera-Pardo, Jaime R.,Trowbridge, Aaron,Nappi, Manuel,Ozaki, Kyohei,Gaunt, Matthew J.
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supporting information
p. 11958 - 11962
(2017/09/20)
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- Substituted Oxopyridine Derivatives and Use Thereof in the Treatment of Cardiovascular Disorders
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The invention relates to substituted oxopyridine derivatives and to processes for their preparation, and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and oedemas, and also ophthalmic disorders.
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Paragraph 1730-1732
(2016/05/02)
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- THERAPEUTIC COMPOUNDS AND USES THEREOF
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The present invention relates to compounds of formula (I): and to salts thereof, wherein R1-R6 have any of the values defined in the specification, and compositions and uses thereof. The compounds are useful as inhibitors of TAF1. Also included are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various TAF1-mediated disorders.
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Page/Page column 90
(2016/08/23)
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- SUBSTITUTED OXOPYRIDINE DERIVATIVES AND USE THEREOF IN THE TREATMENT OF CARDIOVASCULAR DISORDERS
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The invention relates to substituted oxopyridine derivatives and to processes for their preparation, and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and oedemas, and also ophthalmic disorders.
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Paragraph 2532-2535
(2016/10/07)
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- DISUBSTITUTED 3,4-DIAMINO-3-CYCLOBUTENE-1,2-DIONE COMPOUNDS FOR USE IN THE TREATMENT OF CHEMOKINE-MEDIATED PATHOLOGIES
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Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds are disclosed that are represented by general formula (I). Also disclosed, are pharmaceutical compositions including these compounds and methods of using these compounds and compositions for the
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Paragraph 0363; 0365
(2014/10/29)
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- Inhibitors of β-site amyloid precursor protein cleaving enzyme (BACE1): Identification of (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′ H -spiro[chromeno[2,3- b ]pyridine-5,4′-oxazol]-2′-amine (AMG-8718)
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We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2′ side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain Aβ levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.
- Dineen, Thomas A.,Chen, Kui,Cheng, Alan C.,Derakhchan, Katayoun,Epstein, Oleg,Esmay, Joel,Hickman, Dean,Kreiman, Chuck E.,Marx, Isaac E.,Wahl, Robert C.,Wen, Paul H.,Weiss, Matthew M.,Whittington, Douglas A.,Wood, Stephen,Fremeau, Robert T.,White, Ryan D.,Patel, Vinod F.
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p. 9811 - 9831
(2015/02/05)
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- IMIDAZOPYRAZINE SYK INHIBITORS
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Certain imidazopyrazines and pharmaceutical compositions thereof are provided herein. Methods of treating patients suf-fering from certain diseases and disorders responsive to the inhibition of Syk activity, which comprises administering to such patients an amount of an imidazopyrazine compound effective to reduce signs or symptoms of the disease or dis-order are provided.
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Paragraph 0283
(2014/01/08)
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- OXAZOLO [5, 4 -B] PYRIDIN- 5 -YL COMPOUNDS AND THEIR USE FOR THE TREATMENT OF CANCER
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The present invention provides oxazolo[5,4-b]pyridin-5-yl compounds useful in the treatment of cancer.
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Page/Page column 19-20
(2012/06/16)
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- TETRACYCLIC INDOLE DERIVATIVES FOR TREATING HEPATITIS C VIRUS INFECTION
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Tetracyclic indole derivatives of formula (I), pharmaceutically acceptable salts and the pharmaceutical compositions thereof are provided, wherein A, A', G, R1, R15, U, V, V, W, W, X, X', Y, Y' are as defined in the invention. Use of these derivatives for treating hepatitis C virus (HCV) infection is also provided.
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Page/Page column 123-124
(2012/04/17)
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- TETRACYCLIC INDOLE DERIVATIVES AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
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The present invention relates to novel Tetracyclic Indole Derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, A', G, R1, R15, U, V, V', X, X', Y and Y' are as defined herein. The present invention also relates to compositions comprisingat least one Tetracyclic Indole Derivative, and methods of using the Tetracyclic Indole Derivatives for treating or preventing HCV infection in a patient.
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Page/Page column 105
(2012/04/17)
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- TRICYCLIC SPIROCYCLE DERIVATIVES AND METHODS OF USE
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The present invention relates to novel Tricyclic Spirocycle Derivatives, pharmaceutical compositions comprising the Tricyclic Spirocycle Derivatives and the use of these compounds for treating or preventing allergy, an allergy-induced airway response, congestion, a cardiovascular disease, an inflammatory disease, a gastrointestinal disorder, a neurological disorder, a metabolic disorder, obesity or an obesity-related disorder, diabetes, a diabetic complication, impaired glucose tolerance or aired fasting glucose.
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Page/Page column 39
(2011/07/29)
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- NOVEL IMIDAZOTHIAZOLES AND IMIDAZOXAZOLES
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The present invention is directed to novel compounds of formula (I) wherein the variables are as defined herein. The compounds of formula (I) are useful as kinase inhibitors and as such would be useful in treating certain conditions and diseases, especially inflammatory conditions and diseases and proliferative disorders and conditions, for example, cancers.
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Page/Page column 51-52
(2008/12/05)
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- PHENYLMETHYL DERIVATIVES HAVING LIPOXYGENASE INHIBITORY ACTIVITY
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Compounds of the structure where Ar is optionally substituted carbocyclic aryl, 5- or 6-membered heterocyclic aryl, 10-membered bicyclic heterocyclic aryl containing one or two nitrogen atoms, 9- or 10-membered heterocyclic containing one or two nitrogen atoms and optionally containing a further nitrogen or oxygen atom and one oxo or thioxo substituent, benzo[b]furyl, benzo[b]thienyl, A1 is propynylene, methylene, or a valence bond, X is O, S, SO2, or NR2, Y is selected from alkyl, haloalkyl, alkoxy, halogen, and hydrogen, A2 is selected from and methylene where Z is OR5 or NHR5 where R5 is hydrogen or alkyl, R1 is hydrogen, alkyl, or OR5, and m and n are integers having a value of 1 or 2 are potent inhibitors of lipoxygenase enzymes and thus inhibit the biosynthesis of leukotrienes. These compounds are useful in the treatment or amelioration of allergic and inflammatory disease states
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