160801-72-9Relevant academic research and scientific papers
Defining the Determinants of Specificity of Plasmodium Proteasome Inhibitors
Yoo, Euna,Stokes, Barbara H.,De Jong, Hanna,Vanaerschot, Manu,Kumar,Lawrence, Nina,Njoroge, Mathew,Garcia, Arnold,Van Der Westhuyzen, Renier,Momper, Jeremiah D.,Ng, Caroline L.,Fidock, David A.,Bogyo, Matthew
, p. 11424 - 11437 (2018)
The Plasmodium proteasome is an emerging antimalarial target due to its essential role in all the major life cycle stages of the parasite and its contribution to the establishment of resistance to artemisinin (ART)-based therapies. However, because of a similarly essential role for the host proteasome, the key property of any antiproteasome therapeutic is selectivity. Several parasite-specific proteasome inhibitors have recently been reported, however, their selectivity must be improved to enable clinical development. Here we describe screening of diverse libraries of non-natural synthetic fluorogenic substrates to identify determinants at multiple positions on the substrate that produce enhanced selectivity. We find that selection of an optimal electrophilic "warhead" is essential to enable high selectivity that is driven by the peptide binding elements on the inhibitor. We also find that host cell toxicity is dictated by the extent of coinhibition of the human β2 and β5 subunits. Using this information, we identify compounds with over 3 orders of magnitude selectivity for the parasite enzyme. Optimization of the pharmacological properties resulted in molecules that retained high potency and selectivity, were soluble, sufficiently metabolically stable and orally bioavailable. These molecules are highly synergistic with ART and can clear parasites in a mouse model of infection, making them promising leads as antimalarial drugs.
AZALACTAM COMPOUNDS AS HPK1 INHIBITORS
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Page/Page column 54, (2021/11/06)
This invention relates to compounds of general Formula (I) and pharmaceutically acceptable salts thereof, in which R1, R2, R3a, R3b, and R4 are as defined herein, to pharmaceutical compositions comprising such compounds and salts, and to methods of using such compounds, salts and compositions for the treatment of abnormal cell growth, including cancer.
Preparation and biological evaluation of soluble tetrapeptide epoxyketone proteasome inhibitors
Lei, Meng,Zhang, Haoyang,Miao, Hang,Du, Xiao,Zhou, Hui,Wang, Jia,Wang, Xueyuan,Feng, Huayun,Shi, Jingmiao,Liu, Zhaogang,Shen, Jian,Zhu, Yongqiang
, p. 4151 - 4162 (2019/08/07)
A series of novel tetrapeptidyl epoxyketone inhibitors of 20S proteasome was designed and synthesized. To fully understand the SAR, various groups at R1, R2, R3, R4 and R5 positions, including aromatic and aliphatic substituents were designed, synthesized and biologically assayed. Based on the enzymatic results, seven compounds were selected to evaluate their cellular activities and soluble compound 36 showed strong potency against human multiple myeloma (MM) cell lines. Microsomal stability results indicated that compound 36 was more stable in mice, rat and human microsomes than marketed carfilzomib. The in vivo activities of this compound were evaluated with the xenograft mice models of MM cell lines ARH77 and RPMI-8226 with luciferase expression and the T/C value of the two models were 49.5% and 37.6%, respectively. To evaluate the potential cardiovascular toxicity, inhibition of hERG ion channel in HEK293 cells by compound 36 and carfilzomib was carried out. The results indicated that 36 had no binding affinity for the hERG ion channel while carfilzomib could bind it with IC50 of 92.1 μM.
An efficient preparation of novel epoxyketone intermediates for the synthesis of carfilzomib and its derivatives
Du, Xiao,Zhang, Hao-Yang,Lei, Meng,Li, Zi-Yuan,Zhu, Yong-Qiang
, p. 82 - 86 (2016/03/08)
A novel and efficient preparation of epoxyketone intermediates for the synthesis of carfilzomib and its derivatives has been developed. Compared to reported methods, this highly stereoselective, environmentally friendly, low-cost method can be used in scaling up the synthesis of carfilzomib and its derivatives.
The synthesis of α,α-disubstituted α-amino acids via ichikawa rearrangement
Szczes?niak, Piotr,Pieczykolan, Micha?,Stecko, Sebastian
, p. 1057 - 1074 (2016/02/19)
An approach to α,α-disubstituted α-amino acids is reported. The key step is allyl cyanate-to-isocyanate rearrangement. As demonstrated, the resultant allyl isocyanates can be directly trapped with various nucleophiles, for instance, alcohols, amines, and organometallic reagents, to provide a broad range of N-functionalized allylamines. The developed method has been successfully applied in the synthesis of two bioactive peptides: 2-aminoadamantane-2-carboxylic acid derived P2X7-evoked glutamate release inhibitor and 4-amino-tetrahydropyranyl-4-carboxylic acid derived dipeptide GSK-2793660, which is currently in clinical trials as cathepsin C inhibitor for the treatment of cystic fibrosis, noncystic fibrosis bronchiectasis, ANCA-associated vasculitis and bronchiectasis.
SUBSTITUTED AMINOPYRIMIDINE COMPOUNDS AND METHODS OF USE
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Paragraph 0498; 0499, (2015/03/31)
The invention relates to the preparation and use of new aminopyrimidine derivatives as drug candidates in free form or in pharmaceutically acceptable salt form and formulations thereof for the modulation of a disorder or disease which is mediated by the activity of the PI3K enzymes. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of disorders or diseases, such as disorders of immunity and inflammation in which PI3K enzymes play a role in leukocyte function, and hyperproliferative disorders associated with PI3K activity, including but not restricted to leukemias and solid tumors, in mammals, especially humans.
CATHEPSIN C INHIBITORS
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Page/Page column 30, (2012/08/28)
Disclosed are 4-amino-2-butenamides of Formula (I) having pharmacological activity, pharmaceutical compositions containing them, and methods for the treatment of diseases mediated by the cathepsin C enzyme such as chronic obstructive pulmonary disease.
INDAZOLYL ESTER AND AMIDE DERIVATIVES FOR THE TREATMENT OF GLUCOCORTICOID RECEPTOR MEDIATED DISORDERS
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Example 95, (2008/12/06)
Compounds of formula (I): The present invention relates to novel indazolyl ester or amide derivatives, to pharmaceutical compositions comprising such derivatives, to processes for preparing such novel derivatives and to the use of such derivatives as medicaments
Synthesis and dipeptidyl peptidase inhibition of N-(4-substituted-2,4-diaminobutanoyl)piperidines
Soroka, Anna,der Veken, Pieter Van,Meester, Ingrid De,Lambeir, Anne-Marie,Maes, Marie-Berthe,Scharpe, Simon,Haemers, Achiel,Augustyns, Koen
, p. 4777 - 4779 (2007/10/03)
In this paper, we report the synthesis of diastereomerically pure N-(4-substituted-2,4-diaminobutanoyl)piperidines. These compounds were prepared to investigate the influence of the 4-substitution on the dipeptidyl peptidase II (DPP II) activity and selectivity of the parent N-(2,4-diaminobutanoyl)piperidine. The (4S)-methyl compound showed subnanomolar inhibition, comparable with the parent compound. The (4R)-methyl group or bigger substituents decreased the activity.
Inhibitors of hepatitis C virus NS3·4A protease 2. Warhead SAR and optimization
Perni, Robert B.,Pitlik, Janos,Britt, Shawn D.,Court, John J.,Courtney, Lawrence F.,Deininger, David D.,Farmer, Luc J.,Gates, Cynthia A.,Harbeson, Scott L.,Levin, Rhonda B.,Lin, Chao,Lin, Kai,Moon, Young-Choon,Luong, Yu-Ping,O'Malley, Ethan T.,Rao, B. Govinda,Thomson, John A.,Tung, Roger D.,Van Drie, John H.,Wei, Yunyi
, p. 1441 - 1446 (2007/10/03)
The α-ketoamide warhead (e.g., 15) was found to be a practical replacement for aliphatic aldehydes in a series of HCV NS3·4A protease inhibitors. Structure-activity relationships and prime side optimization are discussed.
