20698-04-8Relevant academic research and scientific papers
TAU-PROTEIN TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
-
Paragraph 0973; 0974, (2021/02/12)
The present disclosure relates to bifunctional compounds, which find utility as modulators of tan protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tan protein, such that tan protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tan. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tan protein. Diseases or disorders that result from aggregation or accumulation of tan protein are treated or prevented with compounds and compositions of the present disclosure.
Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties
Soth, Michael J.,Le, Kang,Di Francesco, Maria Emilia,Hamilton, Matthew M.,Liu, Gang,Burke, Jason P.,Carroll, Chris L.,Kovacs, Jeffrey J.,Bardenhagen, Jennifer P.,Bristow, Christopher A.,Cardozo, Mario,Czako, Barbara,De Stanchina, Elisa,Feng, Ningping,Garvey, Jill R.,Gay, Jason P.,Do, Mary K. Geck,Greer, Jennifer,Han, Michelle,Harris, Angela,Herrera, Zachary,Huang, Sha,Giuliani, Virginia,Jiang, Yongying,Johnson, Sarah B.,Johnson, Troy A.,Kang, Zhijun,Leonard, Paul G.,Liu, Zhen,McAfoos, Timothy,Miller, Meredith,Morlacchi, Pietro,Mullinax, Robert A.,Palmer, Wylie S.,Pang, Jihai,Rogers, Norma,Rudin, Charles M.,Shepard, Hannah E.,Spencer, Nakia D.,Theroff, Jay,Wu, Qi,Xu, Alan,Yau, Ju Anne,Draetta, Giulio,Toniatti, Carlo,Heffernan, Timothy P.,Jones, Philip
, p. 12957 - 12977 (2020/11/13)
Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.
Bulk Inclusions of Double Pyridazine Molecular Rotors in Hexagonal Tris(o-phenylene)cyclotriphosphazene
Kaleta, Ji?í,Bastien, Guillaume,Wen, Jin,Dra?ínsky, Martin,Tortorici, Edward,Císa?ová, Ivana,Beale, Paul D.,Rogers, Charles T.,Michl, Josef
, p. 8449 - 8467 (2019/07/03)
A new generation of double pyridazine molecular rotors differing in intramolecular dipole-dipole spacing was synthesized. All rotor molecules formed bulk inclusions in a tris(o-phenylenedioxy)cyclotriphosphazene (TPP) host. Results of dielectric spectroscopy were fitted to a pair of nine-state models that accounted for interactions of neighboring dipoles at either an aligned or opposed possible orientation of the local threefold dipole rotation potentials within a channel of the TPP host. The results indicate dipole-dipole interaction strengths at the 100 to 200 K scale that lead dipoles to preferentially populate a subset of low-energy configurations. They also reveal that pyridazines with ethynyl substituents in 3- and 6-positions have slightly higher rotational barriers (3.2-3.5 kcal/mol) than those carrying one ethynyl and one tert-butyl group (1.9-3.0 kcal/mol). Upon cooling, these barriers reduce the rate of thermal transitions between the potential wells so much that the inclusions cannot achieve ordered dipolar ground states.
TAU-PROTEIN TARGETING PROTACS AND ASSOCIATED METHODS OF USE
-
Paragraph 1259-1260, (2018/05/24)
The present disclosure relates to bifunctional compounds, which find utility as modulators of tau protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tau protein, such that tau protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.
First synthesis of novel 3,3′-bipyridazine derivatives as new potent antihepatocellular carcinoma agents
Yue, Qiming,Zhao, Yi,Hai, Li,Zhang, Tao,Guo, Li,Wu, Yong
, p. 7670 - 7675 (2015/09/07)
Hepatocellular carcinoma is one of the most common kind of cancers in clinical, and its clinical treatment is quite difficult. The latest research suggests that pyridazinone with a novel molecular skeleton shows excellent activity against hepatocellular c
SUBSTITUTED ARYLSULFONYLAMINOMETHYLPHOSPHONIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR USE IN THE TREATMENT OF TYPE I AND II DIABETES MELLITUS
-
Page/Page column 45, (2009/03/07)
The present invention relates to substituted arylsulphonylaminomethylphosphonic acid derivatives of general formula (I) wherein R, X, Y and Z are defined as in claim 1, the tautomers, enantiomers, diastereomers, mixtures thereof and salts thereof which have valuable pharmacological properties, particularly the suppression of the interaction of glycogen phosphorylase a with the GL subunit of glycogen-associated protein phosphatase 1 (PP1), and their use as pharmaceutical compositions.
Spiro Compounds As NPY Y5 Receptor Antagonists
-
Page/Page column 40, (2009/08/18)
The present invention relates to novel compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R is an aryl or heteroaryl, which may be substituted by one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano;Z1 is H, C1-C4 alkyl or F;Z is CH2, CH(C1-C4 alkyl), C(C1-C4 alkyl)2 or a bond;A is a 6-10 membered aryl or heteroaryl, which may be substituted by one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano; or —C(═O)—X; or —O(CH2)0-1R1;B is hydrogen or is a 5-6 membered heteroaryl, or a 4-6 membered heterocycle, or phenyl, which may be substituted by one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, hydroxyl, cyano; A and B being linked via any atom;R1 is —(C1-C4)alkyl(C1-C4)alkoxy; or C3-C8 cycloalkyl; or R1 is an aryl or heteroaryl, which may be substituted by one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano; or R1 is a 4-6 membered heterocycle, which may be substituted by one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano;X is OR2 or NR3R4;R2 is C1-C4 alkyl;R3 is hydrogen or together with R4 and the nitrogen form a 5-6 saturated membered ring;R4 is C3-C8 cycloalkyl; processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as NPY Y5 receptor antagonists and as agents for the treatment and/or prophylaxis of eating disorders such as a binge eating disorder.
NEW PYRIDAZINE DERIVATIVES WITH MCH ANTAGONISTIC ACTIVITY AND MEDICAMENTS COMPRISING THESE COMPOUNDS
-
Page/Page column 69, (2008/12/06)
The present invention relates to compounds of general formula I wherein the groups and radicals B, W, X, Y, Z, R1, R2, have the meanings given in claim 1. Moreover the invention relates to pharmaceutical compositions containing at least one compound according to the invention. By virtue of their MCH-receptor antagonistic activity the pharmaceutical compositions according to the invention are suitable for the treatment of metabolic disorders and/or eating disorders, particularly obesity, bulimia, anorexia, hyperphagia and diabetes.
(HETERO)ARYL COMPOUNDS WITH MCH ANTAGONISTIC ACTIVITY AND MEDICAMENTS COMPRISING THESE COMPOUNDS
-
Page/Page column 91, (2010/11/27)
The present invention relates to (hetero)aryl compounds of general formula (I) wherein the groups and radicals A, B, Q, W, X, Y, Z, R1, R2, R4a, R4b, R5a, R5b, have the meanings given in cl
Dramatically enhanced fluorescence of heteroaromatic chromophores upon insertion as spacers into oligo(triacetylene)s
Edelmann, Michael J.,Raimundo, Jean-Manuel,Utesch, Nils F.,Diederich, Francois,Boudon, Corinne,Gisselbrecht, Jean-Paul,Gross, Maurice
, p. 2195 - 2213 (2007/10/03)
In continuation of a previous study on the modulation of π-electron conjugation of oligo(triacetylene)s by insertion of central hetero-spacer fragments between two (E)-hex-3-ene-1,5-diyne ((E)-1,2-diethynylethene, DEE) moieties (Fig. 1), a new series of trimeric hybrid oligomers (14-18 and 22-24, Fig. 2) were prepared (Schemes 1-3). Spacers used were both electron-deficient (quinoxaline-based heterocycles, pyridazine) and electron-rich (2,2′-bithiophene, 9,9-dioctyl-9H-fluorene) chromophores. With 19-21 (Scheme 4), a series of transition metal complexes was synthesized as potential precursors for nanoscale scaffolding based on both covalent acetylenic coupling and supramolecular assembly. The UV/VIS spectra (Fig. 3) revealed that the majority of spacers provided heterotrimers featuring extended π-electron delocalization. The new hybrid chromophores show a dramatically enhanced fluorescence compared with the DEE dimer 13 and homo-trimer 12 (Fig. 5). This increase in emission intensity appears as a general feature of these systems: even if the spacer molecule is non-fluorescent, the corresponding hetero-trimer may show a strong emission (Table 2). The redox properties of the new hybrid chromophores were determined by cyclic voltammetry (CV) and rotating-disk voltammetry (RDV) (Table 3 and Fig. 5). In each case, the first one-electron reduction step in the hetero-trimers appeared anodically shifted compared with DEE dimer 13 and homo-trimer 12. With larger spacer chromophore extending into two dimensions (as in 14-18, Fig. 2), the anodic shift (by 240-490 mV, Table 3) seems to originate from inductive effects of the two strongly electron-accepting DEE substituents rather than from extended π-electron conjugation along the oligomeric backbone, as had previously been observed for DEE-substituted porphyrins.
