- Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of non-small cell lung cancer
-
Valosine containing protein (VCP/p97) is a member of the AAA ATPase family involved in several essential cellular functions and plays an important role in the ubiquitin-mediated degradation of misfolded proteins. P97 has a significant role in maintaining the cellular protein homeostasis for tumor cell growth and survival and has been found overexpressed in many tumor types. No new molecule entities based on p97 target were approved in clinic. Herein, a series of novel pyrimidine structures as p97 inhibitors were designed and synthesized. After enzymatic evaluations, structure-activity relationships (SAR) were discussed in detailed. Among the screened compounds, derivative 35 showed excellent enzymatic inhibitory activity (IC50, 36 nM). The cellular inhibition results showed that compound 35 had good antiproliferative activity against the non-small cell lung cancer A549 cells (IC50, 1.61 μM). Liver microsome stability showed that the half-life of compound 35 in human liver microsome was 42.3 min, which was more stable than the control CB-5083 (25.8 min). The in vivo pharmacokinetic results showed that the elimination phase half-lives of compound 35 were 4.57 h for ig and 3.64 h for iv, respectively and the oral bioavailability was only 4.5%. These results indicated that compound 35 could be effective for intravenous treatment of non-small cell lung cancer.
- Wang, Xueyuan,Bai, Enhe,Zhou, Hui,Sha, Sijia,Miao, Hang,Qin, Yanru,Liu, Zhaogang,Wang, Jia,Zhang, Haoyang,Lei, Meng,Liu, Jia,Hai, Ou,Zhu, Yongqiang
-
-
Read Online
- AROMATIC DERIVATIVES, PREPARATION METHODS, AND MEDICAL USES THEREOF
-
The present disclosure relates generally to aromatic derivatives that are inhibitors of FGFR4 and are useful in treating FGFR4-associated diseases or conditions. Compositions containing the compounds of the present disclosure are also provided.
- -
-
Paragraph 0176
(2020/09/19)
-
- Discovery and Optimization of Glucose Uptake Inhibitors
-
Aerobic glycolysis, originally identified by Warburg as a hallmark of cancer, has recently been implicated in immune cell activation and growth. Glucose, the starting material for glycolysis, is transported through the cellular membrane by a family of glucose transporters (GLUTs). Therefore, targeting glucose transporters to regulate aerobic glycolysis is an attractive approach to identify potential therapeutic agents for cancers and autoimmune diseases. Herein, we describe the discovery and optimization of a class of potent, orally bioavailable inhibitors of glucose transporters, targeting both GLUT1 and GLUT3.
- Liu, Kevin G.,Kim, Ji-In,Olszewski, Kellen,Barsotti, Anthony M.,Morris, Koi,Lamarque, Christophe,Yu, Xuemei,Gaffney, Jack,Feng, Xiao-Jiang,Patel, Jeegar P.,Poyurovsky, Masha V.
-
supporting information
p. 5201 - 5211
(2020/07/10)
-
- Preparation method of polymerase inhibitor used for tumor-related diseases
-
The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of a terminal anchor polymerase inhibitor with a structure shown in a formula I. The prepared compound has certain inhibitory activity against both PARP1 and PARP2.
- -
-
Paragraph 0022; 0026; 0027
(2019/11/14)
-
- Polymerase inhibitor used for treating tumor-related diseases
-
The invention belongs to the field of medicinal chemistry, and particularly relates to a tankyrase inhibitor of a structure as shown in a formula I. The compound shows certain inhibiting activity to both PARP1 and PARP2.
- -
-
Paragraph 0038; 0042-0043
(2019/11/13)
-
- HETEROCYLCOALKENYL DERIVATIVES USEFUL AS AGONISTS OF THE GPR120 AND / OR GPR40
-
The present invention is directed to heterocycloalkenyl derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the GPR120 and / or GPR40 receptors. 5 More particularly, the compound
- -
-
Page/Page column 82-83
(2019/10/01)
-
- Discovery of Orally Bioavailable and Liver-Targeted Hypoxia-Inducible Factor Prolyl Hydroxylase (HIF-PHD) Inhibitors for the Treatment of Anemia
-
We report herein the design and synthesis of a series of orally active, liver-targeted hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors for the treatment of anemia. In order to mitigate the concerns for potential systemic side effects, we
- Liu, Ping,Wang, Liping,Dubois, Byron G.,Colandrea, Vincent J.,Liu, Rongqiang,Cai, Jiaqiang,Du, Xiaoxing,Quan, Weiguo,Morris, William,Bai, Jianwu,Bishwokarma, Bimjhana,Cheng, Mangeng,Piesvaux, Jennifer,Ray, Kallol,Alpert, Carla,Chiu, Chi-Sung,Zielstorff, Mark,Metzger, Joseph M.,Yang, Liming,Leung, Dennis,Alleyne, Candice,Vincent, Stella H.,Pucci, Vincenzo,Li, Xiaofang,Crespo, Alejandro,Stickens, Dominique,Hale, Jeffrey J.,Ujjainwalla, Feroze,Sinz, Christopher J.
-
supporting information
p. 1193 - 1198
(2018/12/11)
-
- Tankyrase inhibitor
-
The invention belongs to the technical field of medicine and specifically relates to a tankyrase inhibitor represented as a general formula (I) and pharmaceutically acceptable salts, esters, solvated compounds or stereisomers of the tankyrase inhibitor, wherein R1, R2, X1, X2, Y1, Y2, Y3, Y4, Z, L, n and A are defined as in the description. The invention also relates to preparation methods of the compounds, pharmaceutical preparations and pharmaceutical compositions containing the compounds, and applications of the compounds and the pharmaceutically acceptable salts, esters, solvated compounds or the stereoisomers of the compounds in preparing medicines of curing and/or preventing cancers and related diseases which are mediated by tankyrase.
- -
-
Paragraph 0390-0393
(2018/02/04)
-
- Tankyrase inhibitor
-
The invention belongs to the technical field of medicines and particularly relates to a tankyrase inhibitor shown in the general formula (I) and pharmaceutically acceptable salt, ester, solvates or stereisomers thereof, wherein R1, R2, R3, R4, R5, m, n, p, Z, L, X and Y are defined in the description. The invention also relates to a preparation of the compounds, a drug preparation and a drug composition containing the compounds and application of the compounds, the pharmaceutically acceptable salt, ester, solvates or stereisomers thereof in preparation of a drug for treating and/or preventing cancer mediated by tankyrase and relevant diseases.
- -
-
Paragraph 0133-0135
(2017/10/31)
-
- NOVEL DIHYDROPYRANOPYRIMIDINONE DERIVATIVES, AND USE THEREOF
-
The present invention relates to a novel dihydropyranopyrimidinone derivative, a tautomer thereof, a stereoisomer thereof and their mixture, or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition for preventing or treating a tankyrase-related disease, which contains the same as an active ingredient.
- -
-
Paragraph 121; 122; 123
(2017/07/01)
-
- TREATMENT OF INFECTIOUS DISEASES WITH GLUCOSE UPTAKE INHIBITORS
-
Provided are methods of treating infectious diseases in mammals comprising administering a compound that inhibits glucose uptake. Particular infectious diseases that may be treated include malaria, leishmaniasis, African trypanosomiasis, tuberculosis, HIV, HCMV or herpes virus. In a first aspect, the invention features a method of treating infectious diseases in a mammal, comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug, wherein the compound is an inhibitor of glucose uptake.
- -
-
Paragraph 0254; 0255
(2017/01/09)
-
- GLUCOSE UPTAKE INHIBITORS
-
Provided hererin are compounds that modulate glucose uptake activityand are useful for treating cancer, autoimmune diseases, inflammation, infectious diseases, and metabolic diseases. In certain embodiments, the compounds modulate glucose uptake activity by modulating cellular components, including, but not limited to those related to glycolysis and known transporters/co-transporters of glucose such as GLUT1 and other GLUT family members/alternative hexose transporters. In certain embodiments, the compounds have the structure of formula I: Formula (I) wherein the variables have the values disclosed herein.
- -
-
Paragraph 0520-0521
(2017/01/09)
-
- Promoting reductive tandem reactions of nitrostyrenes with Mo(CO)6 and a palladium catalyst to produce 3 h -indoles
-
The combination of Mo(CO)6 and 10 mol % of palladium acetate catalyzes the transformation of 2-nitroarenes to 3H-indoles through a tandem cyclization-[1,2] shift reaction of in situ generated nitrosoarenes. Mo(CO)6 appears to have dual roles in this transformation: generate CO and promote C-N bond formation to increase the yield of the N-heterocycle product.
- Jana, Navendu,Zhou, Fei,Driver, Tom G.
-
supporting information
p. 6738 - 6741
(2015/06/16)
-
- Rh2(II)-catalyzed ester migration to afford 3 H-indoles from trisubstituted styryl azides
-
Rh2(II)-Complexes trigger the formation of 3H-indoles from ortho-alkenyl substituted aryl azides. This reaction occurs through a 4π-electron-5-atom electrocyclization of the rhodium N-aryl nitrene followed by a [1,2]-migration to afford only 3H-indoles. The selectivity of the migration is dependent on the identity of the β-styryl substituent.
- Kong, Chen,Driver, Tom G.
-
supporting information
p. 802 - 805
(2015/04/27)
-
- FUSED PYRIMIDINES AS INHIBITORS OF p97 COMPLEX
-
Fused pyrimidine compounds having a saturated, unsaturated or aromatic A ring fused to a pyrimidine ring and having a complex substituents at the 2 position and a substituted amine at the 4 position of the pyrimidine ring as well as optional aliphatic, functional and/or aromatic components substituted at other positions of the pyrimidine ring and A ring are disclosed. These compounds are inhibitors of the AAA proteasome complex containing p97 and are effective medicinal agents for treatment of diseases associated with p97 bioactivity such as cancer.
- -
-
Page/Page column 183
(2014/02/15)
-
- 4-OXO-3,5,7,8-TETRAHYDRO-4H-PYRANO {4,3-D} PYRMINIDINYL COMPOUNDS FOR USE AS TANKYRASE INHIBITORS
-
The present invention provides for compounds of formula (I) wherein R1 and R2 are defined herein. The present invention also provides for pharmaceutical compositions and combinations comprising a compound of formula (I) as well as fo
- -
-
Page/Page column 26
(2013/03/26)
-
- NOVEL 2-PIPERIDIN-1-YL-ACETAMIDE COMPOUNDS FOR USE AS TANKYRASE INHIBITORS
-
The present invention provides for compounds of formula (I), wherein R1-R5 and L are defined herein. The present invention also provides for pharmaceutical compositions and combinations comprising a compound of formula (I) as well as for the use of such compounds as tankyrase inhibitors and in the treatment of Wnt signaling and tankyrase 1 and 2 signaling related disorders which include, but are not limited to, cancer.
- -
-
Page/Page column 40
(2013/03/26)
-
- CHEMOKING RECEPTOR ANTAGONISTS
-
Disclosed herein are chemokine receptor antagonists of formula (I) wherein G1, X1, X2, and X3 are as defined in the specification. Compositions comprising such compounds; and methods for treating conditions and disorders using such compounds and compositions are also described.
- -
-
Page/Page column 254
(2013/03/26)
-
- 4 - PIPERIDINYL COMPOUNDS FOR USE AS TANKYRASE INHIBITORS
-
The present invention provides for compounds of formula (I).The present invention also provides for pharmaceutical compositions and combinations comprising a compound of formula (I) as well as for the use of such compounds as tankyrase inhibitors and in the treatment of Wnt signaling and tankyrase 1 and 2 signaling related disorders which include, but are not limited to, cancer.
- -
-
Page/Page column 35
(2013/03/26)
-
- Synthesis, preliminary biological evaluation and molecular modeling of some new heterocyclic inhibitors of TACE
-
Central heteroaryl ring analogues belonging to a series of potent hydroxamate TACE inhibitors were synthesized. The TACE inhibitory activities of these compounds were evaluated by in vitro WBA and in silico molecular modeling studies using crystal structure of human TACE. Compound 14 showed very good in vitro inhibition, supported by the in silico docking studies.
- Sengupta, Prabal,Puri, Chetan S.,Chokshi, Hemant A.,Sheth, Chetana K.,Midha, Ajay S.,Chitturi, Trinadha Rao,Thennati, Rajamannar,Murumkar, Prashant R.,Yadav, Mange Ram
-
experimental part
p. 5549 - 5555
(2011/12/15)
-
- NOVEL COMPOUNDS AND METHODS OF USING THEM
-
The present invention relates to novel compounds and their pharmaceutically acceptable salts, prodrugs, solvates, polymorphs, tautomers and isomers. In some embodiments, the compounds described herein may be used to modulate sirtuins (SIRT). The present i
- -
-
Page/Page column 103
(2009/05/28)
-
- Beta-sulfonamide hydroxamic acid inhibitors of tace/matrix metalloproteinase
-
This invention provides compounds of Formula I, having the structure: that are useful in treating diseases or disorders mediated by TNF-α, such as arthritis (rheumatoid arthritis (RA), juvenile RA, psoriatic arthritis, osteoarthritis etc), tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection, ankylosing spondylitis, psoriasis, sepsis, multiple sclerosis, Crohn's disease, degenerative cartilage loss, asthma, idiopathic pulmonary fibrosis, vasculitis, systemic lupus erythematosus, irritable bowel syndrome, acute coronary syndrome, hepatitis C, cachexia, COPD, stroke or type 2 diabetes, and for alleviation of symptoms thereof. The invention further provides methods for use of the compounds.
- -
-
Page/Page column 37
(2008/06/13)
-
- Niacin receptor agonists, compositions containing such compounds and methods of treatment
-
The present invention encompasses compounds of Formula I: as well as pharmaceutically acceptable salts and hydrates thereof, that are useful for treating atherosclerosis, dyslipidemias and the like. Pharmaceutical compositions and methods of use are also included.
- -
-
Page/Page column 33; 54
(2010/11/25)
-
- Free Radical Ring-Expansion Leading to Novel Six- and Seven-Membered Heterocycles
-
Free radical promoted ring-expansion of nitrogen-, oxygen- and sulfur-containing heterocyclic β-keto esters is described.Treatment of the derived phenylselenomethyl derivatives with tri-n-butyltin hydride leads to smooth one-carbon ring expansion.
- Dowd, Paul,Choi, Soo-Chang
-
p. 4847 - 4860
(2007/10/02)
-