- MODIFIED PROTEINS AND PROTEIN DEGRADERS
-
Provided herein are compounds, pharmaceutical compositions, and methods for binding or degrading target proteins. Further provided herein are compounds having a DNA damage-binding protein 1 (DDB1) binding moiety. Some such embodiments include a linker. Some such embodiments include a target protein binding moiety. Further provided herein are ligand-DDB1 complexes. Further provided herein are in vivo modified DDB1 proteins.
- -
-
Paragraph 00639-00641
(2021/12/08)
-
- ARYL AND HETEROARYL-CARBOXAMIDE SUBSTITUTED HETEROARYL COMPOUNDS AS TYK2 INHIBITORS
-
Novel carboxamide substituted compounds of Formula (I) are disclosed; as well as processes for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Tyrosine Kinase 2 (Tyk2).
- -
-
Page/Page column 130
(2021/10/15)
-
- Extended structure-activity study of thienopyrimidine-based EGFR inhibitors with evaluation of drug-like properties
-
Thieno[2,3-d]pyrimidines are attractive derivatives for cancer treatment, among others through regulation of the epidermal growth factor receptor tyrosine kinase (EGFR-TK). In an extended SAR study, 44 new compounds of this class have been evaluated as inhibitors, while simultaneously focussing on ADME properties. Through the application of bioisosters, hybrid structures, solubilizing tails, and a combination approach several successful alterations in terms of activity and physiochemical properties were accomplished. Compounds based on benzylamines were found superior to aniline hybrid structures with respect to activity and ADME profile. Exploration of the former class revealed meta-and para amides as favourable 6-aryl substituents, contributing to an increase in activity and acting as a linker for solubilizing tails. Next, combinations of activity-inducing groups on the same scaffold resulted in new drug candidates. Compounds containing 6-aryls with the (2-(dimethylamino)ethyl)carbamoyl substituent were found equipotent to Erlotinib. Compared to this commercial drug, improved solubility and metabolic stability were observed. However, the thieno[2,3-d]pyrimidines with a solubilizing tail was by Caco-2 experiments found to have permeability issues, making further drug development difficult. Selected compounds were further analysed for toxicity and teratogenicity in zebrafish embryos. Two thienopyrimidines were both found to be less lethal than Erlotinib and to perform as well in terms of teratogenicity. Finally, the most promising thienopyrimidine drug was evaluated in a panel of human cancer cell lines, showing a clear potential for thienopyrimidines as anti-cancer agents.
- Bugge, Steffen,Buene, Audun Formo,Jurisch-Yaksi, Nathalie,Moen, Ingri Ullestad,Skj?nsfjell, Ellen Martine,Sundby, Eirik,Hoff, B?rd Helge
-
p. 255 - 274
(2015/11/27)
-
- Synthesis, biological activity and molecular modeling of new biphenylic carboxamides as potent and selective CB2 receptor ligands
-
The CB2 receptor is a therapeutic target of increasing importance for several diseases, including pain, inflammation, neurodegeneration, cancer and osteoporosis. While several compounds showing CB2-selective agonist or inverse agonist properties have been developed, only few CB2 receptor selective neutral antagonists are actually known. Such type of compounds could be useful to study more in depth the role of the CB2 receptor, because they lack the ability to counteract its g €constitutiveg € activity. Here we describe the synthesis and biological activity of a series of biphenylic carboxamides as a new class of CB2 receptor selective ligands. In binding assays, one of these compounds showed good CB2 receptor affinity and selectivity (Ki Combining double low line 11.48 nM; Selectivity Index Combining double low line 130). Furthermore, in functional assays, the same compound showed a very interesting pharmacological profile as CB2 receptor selective neutral antagonist. These results pave the way to further developments, including structural optimization, with the aim to obtain more potent CB2 receptor ligands with this peculiar feature.
- Bertini, Simone,Parkkari, Teija,Savinainen, Juha R.,Arena, Chiara,Saccomanni, Giuseppe,Saguto, Simone,Ligresti, Alessia,Allarà, Marco,Bruno, Agostino,Marinelli, Luciana,Di Marzo, Vincenzo,Novellino, Ettore,Manera, Clementina,Macchia, Marco
-
p. 526 - 536
(2015/02/19)
-
- HYDROXYPHENYLSULFONAMIDES AS ANTIAPOPTOTIC BCL INHIBITORS
-
The present invention provides compound of Formula (I): or a stereoisomer, tautomer, salt or solvate thereof, wherein the variables are defined herein. The compounds of formula (I) are inhibitors of Bcl-2 family antiapoptotic proteins, compositions containing the compounds and methods of treating diseases using the compounds.
- -
-
Page/Page column 198
(2010/01/07)
-
- METHODS OF TREATING ALPHA ADRENERGIC MEDIATED CONDITIONS
-
Described herein are compounds for and methods of treating conditions or diseases in a subject by administering to the subject a pharmaceutical composition containing an effective amount of an α-adrenergic modulator. The compounds and methods are also use
- -
-
Page/Page column 8-9
(2009/12/24)
-
- ARYL FLUOROETHYL UREAS ACTING AS ALPHA 2 ADRENERGIC AGENTS
-
The invention provides well-defined aryl fluoroethyl ureas that are useful as selective alpha2 adrenergic agonists. As such, the compounds described herein are useful in treating a wide variety of disorders associated with modulation of alpha2 adrenergic receptors.
- -
-
Page/Page column 22-23
(2008/12/07)
-
- Novel synthetic analogs of the Pseudomonas autoinducer
-
Release of virulence factors in Pseudomonas aeruginosa is regulated by two N-acylhomoserine lactones, PAI-1 and PAI-2, that activate the respective transcription factors LasR and Rh1R. With the goal of developing novel therapeutic agents, we synthesized constrained analogs of PAI-1 and evaluated them in P. aeruginosa. Two of the novel analogs bound to LasR and showed agonist activity in LasR stimulation of a lasI-lacZ reporter construct.
- Kline,Bowman,Iglewski,De Kievit,Kakai,Passador
-
p. 3447 - 3452
(2007/10/03)
-
- Marine Bacteria, I. - Synthesis of Pentabromopseudiline, a Cytotoxic Phenylpyrrole from Alteromonas luteo-violaceus
-
A new synthesis of 2,3,4-tribromo-5-(3,5-dibromo-2-hydroxyphenyl)pyrrole (1a, pentabromopseudiline), an antibiotic, enzymeinhibitory and cytotoxic active constituent of the marine bacterium Alteromonas luteo-violaceus, is described.For investigation of structure-activity relationships further 2-phenylpyrroles are investigated.Key step in their synthesis is the Grignard reaction of 2-(1,3-dioxan-2-yl)ethylmagnesium bromide (9d) with benzoyl chlorides yielding γ-phenyl-γ-ketoaldehydes 24, and the Paal-Knorr cyclisation of the latter. - Key Words: Alteromonas luteo-violaceus / Bromopyrrole / Marine bacteria / Pentabromopseudiline
- Laatsch, Hartmut,Pudleiner, Heinz
-
p. 863 - 882
(2007/10/02)
-