- Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors
-
Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinase inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In this study, we successfully engaged a structure-based drug design approach to discover macrocyclic pyrimidines as potent Mer tyrosine kinase (MerTK)-specific inhibitors. An enzyme-linked immunosorbent assay (ELISA) in 384-well format was employed to evaluate the inhibitory activity of macrocycles in a cell-based assay assessing tyrosine phosphorylation of MerTK. Through structure–activity relationship (SAR) studies, analogue 11 [UNC2541; (S)-7-amino-N-(4-fluorobenzyl)-8-oxo-2,9,16-triaza-1(2,4)-pyrimidinacyclohexadecaphane-1-carboxamide] was identified as a potent and MerTK-specific inhibitor that exhibits sub-micromolar inhibitory activity in the cell-based ELISA. In addition, an X-ray structure of MerTK protein in complex with 11 was resolved to show that these macrocycles bind in the MerTK ATP pocket.
- McIver, Andrew L.,Zhang, Weihe,Liu, Qingyang,Jiang, Xinpeng,Stashko, Michael A.,Nichols, James,Miley, Michael J.,Norris-Drouin, Jacqueline,Machius, Mischa,DeRyckere, Deborah,Wood, Edgar,Graham, Douglas K.,Earp, H. Shelton,Kireev, Dmitri,Frye, Stephen V.,Wang, Xiaodong
-
supporting information
p. 207 - 213
(2017/02/15)
-
- Atorvastatin that non-preparation method
-
The invention relates to a preparation method of avanafil and a new compound provided in a preparation process. According to the method, 5-uracil carboxylic acid or an ester thereof is taken as the raw material, and the avanafil meeting the clinical requirements can be synthesized at a relatively cost; besides, the preparation method is simple and convenient to operate, mild in reaction conditions, high in yield, low in cost, environmentally friendly and suitable for industrial large-scale production of the avanafil.
- -
-
Paragraph 0058-0060
(2017/07/01)
-
- PHARMACEUTICAL COMPOUNDS
-
The present invention relates to compounds that are useful as inhibitors of the activity of Wee-1 kinase. The present invention also relates to pharmaceutical compositions comprising these compounds and to methods of using these compounds in the treatment of cancer and methods of treating cancer.
- -
-
Page/Page column 66
(2015/02/25)
-
- THERAPUETIC USES OF SELECTED PYRIMIDINE COMPOUNDS WITH ANTI-MER TYROSINE KINASE ACTIVITY
-
Uses of pyrimidines with anti-Mer tyrosine kinase activity as anti-infective agents, immunostimulatory and immunomodulatory agents, anti-cancer agents (including against MerTK -/- tumors and ITD and TKD mutant forms of Acute Myeloid Leukemia (AML)), and as adjunctive agents in combination with chemotherapeutic, radiation or other standard of care for neoplasms.
- -
-
Page/Page column 293
(2015/11/03)
-
- 2,4-Pyrimidinediamine Compounds and Their Uses
-
The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.
- -
-
Paragraph 0367
(2015/11/10)
-
- PYRIMIDINE COMPOUNDS FOR THE TREATMENT OF CANCER
-
Compounds of Formula I or II: are described, along with pharmaceutical compositions containing the same and methods of using such compounds for the treatment of cancer.
- -
-
Page/Page column 53; 54
(2014/06/23)
-
- 8-ETHYL-6-(ARYL)PYRIDO [2,3-D]PYRIMIDIN-7(8H) -ONES FOR THE TREATMENT OF NERVOUS SYSTEM DISORDERS AND CANCER
-
Provided herein are PAK inhibitors and methods of utilizing PAK inhibitors for the treatment of CNS disorders such as neuropsychiatric disorders or neurofibromatosis. Also described herein are methods of utilizing PAK inhibitors for the treatment of cancer.
- -
-
Paragraph 00569
(2013/04/10)
-
- HETEROCYCLIC UREA COMPOUNDS
-
The present invention provides a compound of the following formula, racemates, enantiomers and salts thereof. Also provided is the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture
- -
-
Page/Page column 66; 74
(2013/07/05)
-
- ANTINEOPLASTIC DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF
-
The disclosure concerns heterobicyclic compounds of general formula (I) and acid addition salts, hydrates and solvates thereof, as well as enantiomers, diastereoisomers and mixtures thereof. Methods for preparing the compounds, pharmaceutical compositions, and methods of treatment also are disclosed.
- -
-
-
- PYRIMIDINE COMPOUNDS AS TUBERCULOSIS INHIBITORS
-
The present invention relates to compounds II useful as inhibitors of treating tuberculosis. The invention also provides processes for preparing compounds of the invention.
- -
-
-
- Synthesis of 2,4,5-trisubstituted pyrimidines
-
A new series of 2,4,5-trisubstituted pyrimidines incorporating 1,3,4-thiadiazole and 1,2,4-triazole rings were synthesized and characterized by the spectral techniques.
- Pawar,Burungale,Karale
-
p. 133 - 136
(2013/09/23)
-
- NICOTINAMIDE DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF
-
The disclosure relates to compounds of formula (I): wherein A, Z, Z′, L, R2 and R3 are as defined in the disclosure, to compositions comprising said compounds, and to methods for the manufacture and therapeutic use thereof.
- -
-
Page/Page column 18
(2010/09/07)
-
- INHIBITORS OF JAK
-
The present invention is directed to compounds of formula (I) and tautomers and pharmaceutically acceptable salts thereof which are selective inhibitors of JAK. The present invention is also directed to intermediates used in making such compounds, the preparation of such a compound, pharmaceutical compositions containing such a compound, methods of inhibition JAK activity, and methods to prevent or treat a number of conditions mediated at least in part by JAK activity.
- -
-
Page/Page column 73-74
(2010/11/18)
-
- INHIBITORS OF PROTEIN KINASES
-
The present invention is directed to compounds of formula (I)-(II) and pharmaceutically acceptable salts, esters, and prodrugs thereof which are inhibitors of syk and/or JAK kinase. The present invention is also directed to intermediates used in making such compounds, the preparation of such a compound, pharmaceutical compositions containing such a compound, methods of inhibition syk and/or JAK kinase activity, methods of inhibition the platelet aggregation, and methods to prevent or treat a number of conditions mediated at least in part by syk and/or JAK kinase activity, such as undesired thrombosis and Non Hodgkin's Lymphoma.
- -
-
Page/Page column 101
(2009/12/05)
-
- Certain Chemical Entities, Compositions, and Methods
-
Chemical entities that modulate smooth muscle myosin and/or non-muscle myosin, pharmaceutical compositions and methods of treatment of diseases and conditions associated with smooth muscle myosin and/or non-muscle myosin are described.
- -
-
Page/Page column 18
(2009/08/16)
-
- SUBSTITUTED PYRIMIDIN-5-CARBOXAMIDES 281
-
A compound of formula (I): and pharmaceutically-acceptable salts thereof wherein the variable groups are defined within; their use in the inhibition of 11betaHSD1, processes for making them and pharmaceutical compositions comprising them are also described.
- -
-
Page/Page column 47
(2009/10/30)
-
- Ion channel modulators and methods of use
-
In general, the invention relates to compounds useful as ion channel modulators. It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as inhibitors of voltage-gated sodium channels and/or calcium channels.
- -
-
Page/Page column 83-84
(2008/06/13)
-
- Aromatic nitrogen-containing 6-membered cyclic compounds
-
An aromatic nitrogen-containing 6-membered cyclic compound of the formula (I): wherein Ring A is a substituted or unsubstituted nitrogen-containing heterocyclic group; R1 is a substituted or unsubstituted lower alkyl group, —NH—Q—R3 (R3 is a substituted or unsubstituted nitrogen containing heterocyclic group, and Q is a lower alkylene group or a single bond), or —NH—R4 (R4 is a substituted or unsubstituted cycloalkyl group); R2 is a substituted or unsubstituted aryl group; one of Y and Z is ═CH—, and the other is ═N—, or a pharmaceutically acceptable salt thereof, these compounds exhibiting excellent selective PDE V inhibitory activities, and hence, being useful in the prophylaxis or treatment of penile erectile dysfunction, etc.
- -
-
-