126027-07-4Relevant articles and documents
Characterization of the human cytomegalovirus protease as an induced- fit serine protease and the implications to the design of mechanism-based inhibitors
LaPlante, Steven R.,Bonneau, Pierre R.,Aubry, Norman,Cameron, Dale R.,Déziel, Robert,Grand-Ma?tre, Chantai,Plouffe, Céline,Tong, Liang,Kawai, Stephen H.
, p. 2974 - 2986 (1999)
The conformational properties of the N-tert-butylacetyl-L-tert- butylglycyl-L-N(δ),N(δ)-dimethylasparagyl-L-alanyl methyl ketone (MK) 1 and its terminal N-isopropylacetyl analogue 2 were investigated. Whereas these compounds are weak (mM IC50 range) inhibitors of the human cytomegalovirus (HCMV) protease, their activated carbonyl analogues are > 1000-fold more potent (e.g., trifluoromethyl ketone 3, IC50 = 1.1 μM). A combination of NMR techniques demonstrated that MK 2 exists in solution as a relatively rigid and extended peptide structure and that the bulky side chains, notably the P3 tert-butyl group, greatly contribute to maintaining this solution conformation. Furthermore, transferred nuclear Overhauser effect (TRNOE) studies provided an enzyme-bound conformation of MK 2 that was found to be similar to its free solution structure and compares very well to the X-ray crystallographic structure of a related peptidyl inhibitor complexed to the enzyme. The fact that ligands such as MK 2 exist in solution in the bioactive conformation accounts, in part, for the observed inhibitory activity of activated ketone inhibitors bearing comparable peptidyl sequences. Comparison of the X-ray structures of HCMV protease apoenzyme and that of its complex with a related peptidyl α-ketoamide inhibitor allowed for a detailed analysis of the previously reported conformational change of the enzyme upon complexation of inhibitors such as 1 and 3. The above observations indicate that HCMV protease is a novel example of a serine protease that operates by an induced-fit mechanism for which complexation of peptidyl ligands results in structural changes which bring the enzyme to a catalytically active (or optimized) form. Kinetic and fluorescence studies are also consistent with an induced-fit mechanism in which a considerable proportion of the intrinsic ligand-binding energy is used to carry out the conformational reorganization of the protease. Issues related to the rational design of both mechanism- and nonmechanism-based inhibitors of HCMV protease, notably in light of the peptidyl ligand-induced optimization of its catalytic functioning, are discussed.
[1,2,4]TRIAZOLO[1,5-A]PYRIMIDINE COMPOUNDS AND USE IN STABILIZING MICROTUBULES
-
Paragraph 00141; 00142, (2019/09/18)
The present disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Rx-R8 are defined herein. Also provided are compositions comprising a compound described herein and a pharmaceutically effective excipient, methods of stabilizing microtubules in a patient comprising administering to the patient a microtubule-stabilizing amount of a compound described herein, methods of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound described herein, and methods of treating a neurodegenerative disease in a patient comprising administering to the patient a therapeutically effective amount of a compound described herein.
Rhodium catalyzed C-C bond cleavage/coupling of 2-(azetidin-3-ylidene)acetates and analogs
Yang, Xuan,Kong, Wei-Yu,Gao, Jia-Ni,Cheng, Li,Li, Nan-Nan,Li, Meng,Li, Hui-Ting,Fan, Jun,Gao, Jin-Ming,Ouyang, Qin,Xie, Jian-Bo
supporting information, p. 12707 - 12710 (2019/10/28)
The C-C bond cleavage/coupling of 2-(azetidin-3-ylidene)acetates with aryl boronic acids catalyzed by a rhodium complex was studied with a "conjugate addition/β-C cleavage/protonation" strategy.
Design, synthesis and evaluation of photoactivatable derivatives of microtubule (MT)-active [1,2,4]triazolo[1,5-a]pyrimidines
Oukoloff, Killian,Kovalevich, Jane,Cornec, Anne-Sophie,Yao, Yuemang,Owyang, Zachary A.,James, Michael,Trojanowski, John Q.,Lee, Virginia M.-Y.,Smith, Amos B.,Brunden, Kurt R.,Ballatore, Carlo
supporting information, p. 2180 - 2183 (2018/06/07)
The [1,2,4]triazolo[1,5-a]pyrimidines comprise a promising class of non-naturally occurring microtubule (MT)-active compounds. Prior studies revealed that different triazolopyrimidine substitutions can yield molecules that either promote MT stabilization or disrupt MT integrity. These differences can have important ramifications in the therapeutic applications of triazolopyrimidines and suggest that different analogues may exhibit different binding modes within the same site or possibly interact with tubulin/MTs at alternative binding sites. To help discern these possibilities, a series of photoactivatable triazolopyrimidine congeners was designed, synthesized and evaluated in cellular assays with the goal of identifying candidate probes for photoaffinity labeling experiments. These studies led to the identification of different derivatives that incorporate a diazirine ring in the amine substituent at position 7 of the triazolopyrimidine heterocycle, resulting in molecules that either promote stabilization of MTs or disrupt MT integrity. These photoactivatable candidate probes hold promise to investigate the mode of action of MT-active triazolopyrimidines.
6,7-DIHYDRO-4H-PYRAZOLO[1,5-A]PYRAZINE AND 6,7-DIHYDRO-4H-TRIAZOLO[1,5-A]PYRAZINE COMPOUNDS FOR THE TREATMENT OF INFECTIOUS DISEASES
-
, (2018/03/28)
The present invention relates to compounds of the formula (I), or pharmaceutically acceptable salts, enantiomer or diastereomer thereof, wherein R1 to R4 and Q are as described above. The compounds may be useful for the treatment or prophylaxis of hepatitis B virus infection.
6,7-DIHYDRO-4H-PYRAZOLO[1,5-A]PYRAZINE COMPOUNDS FOR THE TREATMENT OF INFECTIOUS DISEASES
-
, (2018/03/26)
The present invention relates to compounds of the formula (I) or pharmaceutically acceptable salts, enantiomer or diastereomer thereof, wherein R1 to R4 are as described above. The compounds may be useful for the treatment or prophylaxis of hepatitis B virus infection.
GLYOXAMIDE SUBSTITUTED PYRROLAMIDE DERIVATIVES AND THE USE THEREOF AS MEDICAMENTS FOR THE TREATMENT OF HEPATITIS B
-
, (2015/02/19)
Inhibitors of HBV replication of Formula (IA), including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein X and R1 to R6 have the meaning as defined herein. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use, alone or in combination with other HBV inhibitors, in HBV therapy.
SULPHAMOYLPYRROLAMIDE DERIVATIVES AND THE USE THEREOF AS MEDICAMENTS FOR THE TREATMENT OF HEPATITIS B
-
, (2015/09/23)
Inhibitors of HBV replication of Formula (A) including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein Ra to Rd, and R5 to R6 have the meaning as defined herein. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use, alone or in combination with other HBV inhibitors, in HBV therapy.
SULPHAMOYLTHIOPHENAMIDE DERIVATIVES AND THE USE THEREOF AS MEDICAMENTS FOR THE TREATMENT OF HEPATITIS B
-
, (2014/12/12)
Inhibitors of HBV replication of formula (I) including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein X and R1 to R8 have the meaning as defined herein. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use, alone or in combination with other HBV inhibitors, in HBV therapy.
SULPHAMOYLPYRROLAMIDE DERIVATIVES AND THE USE THEREOF AS MEDICAMENTS FOR THE TREATMENT OF HEPATITIS B
-
, (2014/12/12)
Inhibitors of HBV replication of Formula (ID) including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein X, Ra to Rd and R4 to R6 have the meaning as defined herein. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use, alone or in combination with other HBV inhibitors, in HBV therapy.
