- Compound for specifically enhancing spatial coupling degree of TRPV4-KCa2.3 complex and application of compound
-
The invention discloses a compound for specifically enhancing the spatial coupling degree of a TRPV4-KCa2.3 complex and an application of the compound, and belongs to the field of chemical medicines.The compound with the structure represented by the general formula (I) is mainly used for uncoupling TRPV4 and KCa2.3 in hypertensive patients, so that two uncoupled proteins can be recoupled, and thenormal state of the two uncoupled proteins can be recovered. Under the normal condition, according to TRPV4 and KCa2.3, TRPV4 receive signals of calcium ions, due to calcium ion inflow, potassium ionoutflow of a downstream KCa2.3 channel is stimulated, vasodilation is achieved through depolarization, and thus the blood pressure of the hypertensive patients is recovered to the normal level.
- -
-
Paragraph 0080-0085
(2021/02/24)
-
- ISOINDOLINONE COMPOUNDS
-
Disclosed herein is a compound or pharmaceutically acceptable salts or stereoisomers thereof of of formula I wherein X1 is linear or branched C1-6 alkyl, C3-6 cycloalkyl, -C1-6 alkyl C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C1-6 alkyl C6-10 aryl, C1-6 alkyl 5-10 membered heteroaryl, wherein X1 is unsubstituted or substituted with one or more of halogen, linear or branched C1-6 alkyl, linear or branched C1-6 heteroalkyl, CF3, CHF2, -O-CHF2, -O-(CH2)2-OMe, OCF3, C1-6 alkylamino, -CN, -N(H)C(O)-C1- 6alkyl, -OC(O)-C1-6alkyl, -OC(O)-C1-4alkylamino, -C(O)O-C1-6alkyl, -COOH, - CHO, -C1-6alkylC(O)OH, -C1-6alkylC(O)O-C1-6alkyl, NH2, C1-6 alkoxy or C1-6 alkylhydroxy; X2 is hydrogen, C6-10 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-C1-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O)-C1-4alkyl-4-8 membered heterocycloalkyl or C6 aryloxy, wherein X2 is unsubstituted or substituted with one or more of linear or branched C1-6 alkyl, NH2, NMe2 or 5-6 membered heterocycloalkyl; n is 0, 1 or 2.
- -
-
Page/Page column 185-186
(2021/04/17)
-
- Design and development of 1,3,4-oxadiazole derivatives as potential inhibitors of acetylcholinesterase to ameliorate scopolamine-induced cognitive dysfunctions
-
The novel hybrids bearing 4-aminopyridine (4-AP) tethered with substituted 1,3,4-oxadiazole nucleus were designed, synthesized, and evaluated for their potential AChE inhibitory property along with significant antioxidant potential. The inhibitory potenti
- Mishra, Puja,Sharma, Piyoosh,Tripathi, Prabhash Nath,Gupta, Sukesh Kumar,Srivastava, Pavan,Seth, Ankit,Tripathi, Avanish,Krishnamurthy, Sairam,Shrivastava, Sushant Kumar
-
-
- Synthesis and Structure–Activity Relationship Studies of Benzo[b][1,4]oxazin-3(4H)-one Analogues as Inhibitors of Mycobacterial Thymidylate Synthase X
-
Since the discovery of a flavin-dependent thymidylate synthase (ThyX or FDTS) that is absent in humans but crucial for DNA biosynthesis in a diverse group of pathogens, the enzyme has been pursued for the development of new antibacterial agents against Mycobacterium tuberculosis, the causative agent of the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous screening efforts and report herein an optimization campaign of a novel series of inhibitors with a unique inhibition profile. The inhibitors display competitive inhibition toward the methylene tetrahydrofolate cofactor of ThyX, enabling us to generate a model of the compounds bound to their target, thus offering insight into their structure–activity relationships.
- Modranka, Jakub,Li, Jiahong,Parchina, Anastasia,Vanmeert, Michiel,Dumbre, Shrinivas,Salman, Mayla,Myllykallio, Hannu,Becker, Hubert F.,Vanhoutte, Roeland,Margamuljana, Lia,Nguyen, Hoai,Abu El-Asrar, Rania,Rozenski, Jef,Herdewijn, Piet,De Jonghe, Steven,Lescrinier, Eveline
-
p. 645 - 662
(2019/02/25)
-
- 4,5-DIHYDROISOXAZOLE DERIVATIVES AS NAMPT INHIBITORS
-
The present invention provides 4,5-dihydroisoxazole derivatives of formula (I), which may be therapeutically useful, more particularly as NAMPT inhibitors. wherein, ring A, L1, L2, X1, X2, X3, Z, R1, R2, R3, R4, R5, m, n, p and q have the meanings given in the specification and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention of diseases or disorder, caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPT) in a mammal. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the substituted 4,5-dihydroisoxazole derivatives of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.
- -
-
Page/Page column 54; 55; 56
(2016/02/26)
-
- SUBSTITUTED OXAZOLE- AND THIAZOLE-BASED CARBOXAMIDE AND UREA DERIVATIVES AS VANILLOID RECEPTOR LIGANDS II
-
The invention relates to oxazole and thiazole-based carboxamide and urea derivatives as vanilloid receptor ligands, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.
- -
-
Page/Page column 38; 40
(2016/06/14)
-
- Preparation of substituted semicarbazides from corresponding amines and hydrazines via phenyl carbamates
-
A simple synthetic procedure for the conversion of amines and hydrazines into substituted semicarbazides was developed. The initial condensation between the desired amine and phenyl chloroformate into phenyl carbamate is followed by the addition of hydrazine under basic conditions. The reaction is tolerable to a variety of functional groups, with mild conditions and high percent yields.
- Hron, Rebecca,Jursic, Branko S.
-
supporting information
p. 1540 - 1543
(2014/03/21)
-
- 4,5-DIHYDROISOXAZOLE DERIVATIVES AS NAMPT INHIBITORS
-
The present invention provides substituted 4,5-dihydroisoxazole derivatives of formula (I), which may be therapeutically useful, more particularly NAMPT inhibitors and in which R1 R2, Y, X, "Het" and "p" have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention of diseases or disorder caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPT) in a mammal. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the substituted 4,5-dihydroisoxazole derivatives of formula (I) or a pharmaceutically acceptable salts or stereoisomers or N-oxide thereof.
- -
-
Paragraph 23
(2014/08/06)
-
- Synthesis and biological evaluation of 4-phenoxy-6,7-disubstituted quinolines possessing semicarbazone scaffolds as selective c-Met inhibitors
-
Novel quinoline derivatives bearing acyclic semicarbazones were prepared and their chemical structures as well as the relative stereochemistry were confirmed. All the synthesized compounds were evaluated for their c-Met kinase inhibitory activity and their cytotoxicity against the cell lines HT-29, MKN-45, and MDA-MB-231 in vitro. Several potent compounds were further evaluated against A549 cells. Most compounds displayed moderate to excellent activity, and the structure-activity relationship studies identified the most promising compound 35 as a selective c-Met kinase inhibitor (IC50 = 4.3 nM). Compound 35 showed a 3.5- and 18.8-fold increase in cytotoxicity in vitro against HT-29 and A549 cells, respectively, compared to that of foretinib. Poor off-target effects of compound 35 were further confirmed by the antiproliferative activity against the c-Met inhibition less sensitive MDA-MB-231 cell line (IC50 = 0.77 μM). Copyright
- Qi, Baohui,Tao, Haiyan,Wu, Di,Bai, Jinying,Shi, Yandan,Gong, Ping
-
p. 596 - 609
(2013/09/02)
-
- Aryl piperazinyl ureas as inhibitors of fatty acid amide hydrolase (FAAH) in rat, dog, and primate
-
A series of aryl piperazinyl ureas that act as covalent inhibitors of fatty acid amide hydrolase (FAAH) is described. A potent and selective (does not inhibit FAAH-2) member of this class, JNJ-40355003, was found to elevate the plasma levels of three fatt
- Keith, John M.,Apodaca, Rich,Tichenor, Mark,Xiao, Wei,Jones, William,Pierce, Joan,Seierstad, Mark,Palmer, James,Webb, Michael,Karbarz, Mark,Scott, Brian,Wilson, Sandy,Luo, Lin,Wennerholm, Michelle,Chang, Leon,Brown, Sean,Rizzolio, Michele,Rynberg, Raymond,Chaplan, Sandra,Breitenbucher, J. Guy
-
supporting information
p. 823 - 827,5
(2020/09/15)
-
- NOVEL PYRIMIDINE COMPOUNDS AS MTOR AND P13K INHIBITORS
-
The present invention relates to pyrimidine compounds of formula (I): which are useful in treating mTOR kinase- or PI3K kinase-related diseases.
- -
-
Page/Page column 140
(2011/07/30)
-
- N- (1, 1, 1, 3, 3, 3-HEXAFLUORO-2-HYDROXYPROPAN-2-YL) BENZYL-N' -ARYLCARBONYLPIPERAZ INE DERIVATIVES
-
101 Abstract. The present invention relates tohexafluoroisopropanol derivativeshaving the general formula I X O N N Y OH F 3 C CF 3 A R 1 R 2 R 3 ( ) n W Z B R 6 5 Formula I to pharmaceutical compositions comprising the same and to the use of these hexafluoroisopropanol derivatives inthe treatment of atherosclerosis
- -
-
Page/Page column 78
(2009/12/23)
-
- N-heteroarylpiperazinyl ureas as modulators of fatty acid amide hydrolase
-
Certain N-heteroarylpiperazinyl urea compounds are described, which are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid
- -
-
Page/Page column 12
(2008/06/13)
-
- PURINE DERIVATIVES AS A2A RECEPTOR AGONISTS
-
A compound of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof.and their preparation and use as A2A receptor agonists
- -
-
Page/Page column 52
(2008/06/13)
-
- CHEMOKINE RECEPTOR BINDING COMPOUNDS
-
The present invention relates to chemokine receptor binding compounds, pharmaceutical compositions and their use. More specifically, the present invention relates to modulators of chemokine receptor activity, preferably modulators of CCR5. Thesd compounds demonstrate protective effects against infection of target cells by a human immunodeficiency virus (HIV).
- -
-
Page/Page column 181
(2008/06/13)
-
- PURINE DERIVATIVES ACTING AS A2A RECEPTOR AGONISTS
-
Compounds of formula (I) in free or salt form, wherein R1, R2 and R3 have the meanings as indicated in the specification, are useful for treating conditions mediated by activation of the adenosine A2A receptor, especially inflammatory or obstructive airways diseases. Pharmaceutical compositions that contain the compounds and a process for preparing the compounds are also described.
- -
-
Page/Page column 51
(2008/06/13)
-
- PIPERAZINYL AND PIPERIDINYL UREAS AS MODULATORS OF FATTY ACID AMIDE HYDROLASE
-
Compounds of formula (I) : wherein, Z is -N-or>CH; R1 is -H or -C1-4alkyl; Ar1 is 2-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-primidinyl, 5-pyrimidinyl, or phenyl, each unsubstituted or substituted at a carbon ring member with one or two Ra moieties; Wher each Ra moiety is independently selected from the group consisting of -C1-4alkyl, -C2-4alkenyl, -OH, -OC1-4alkyl, halo, -CF3, -OCF3, -SCF3, -SH, -S(O)0-2C1-4alkyl, -OSO2C1-4alkyl, -CO2C1-4alkyl, -CO2H, -COC1-4alkyl, -N(Rb)Rc, -SO2NRbRc, -NRbSO2Rc, -C(=O)NRbRc, -NO2, and -CN, wherein Rb and Rc are each independently -H or -C1-4alkyl; and Ar2 is defined in the claims are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat, e.g., anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as multiple sclerosis).
- -
-
Page/Page column 48
(2008/06/13)
-
- Identification and biological evaluation of 4-(3-trifluoromethylpyridin-2- yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide, a high affinity TRPV1 (VR1) vanilloid receptor antagonist
-
High throughput screening using the recombinant human TRPV1 receptor was used to identify a series of pyridinylpiperazine ureas (3) as TRPV1 vanilloid receptor ligands. Exploration of the structure-activity relationships by parallel synthesis identified t
- Swanson, Devin M.,Dubin, Adrienne E.,Shah, Chandra,Nasser, Nadia,Chang, Leon,Dax, Scott L.,Jetter, Michele,Breitenbucher, J. Guy,Liu, Changlu,Mazur, Curt,Lord, Brian,Gonzales, Lisa,Hoey, Kenway,Rizzolio, Michele,Bogenstaetter, Michael,Codd, Ellen E.,Lee, Doo H.,Zhang, Sui-Po,Chaplan, Sandra R.,Carruthers, Nicholas I.
-
p. 1857 - 1872
(2007/10/03)
-
- Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency
-
Starting with our previously described20 class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC50 = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC50 = 41 nM) and its oral bioavailability in mice (20% F) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.
- De Lucca, George V.,Ui, Tae Kim,Vargo, Brian J.,Duncia, John V.,Santella III, Joseph B.,Gardner, Daniel S.,Zheng, Changsheng,Liauw, Ann,Wang, Zhang,Emmett, George,Wacker, Dean A.,Welch, Patricia K.,Covington, Maryanne,Stowell, Nicole C.,Wadman, Eric A.,Das, Anuk M.,Davies, Paul,Yeleswaram, Swamy,Graden, Danielle M.,Solomon, Kimberly A.,Newton, Robert C.,Trainor, George L.,Decicco, Carl P.,Ko, Soo S.
-
p. 2194 - 2211
(2007/10/03)
-
- Semicarbazide derivatives, processes for preparation thereof and pharmaceutical composition comprising the same
-
A compound of the formula: STR1 wherein R 1 is hydrogen,R 2 is hydrogen, lower alkyl, ar(lower)alkyl, lower alkenyl or aryl,R 3 is lower alkyl, ar(lower)alkyl, lower alkenyl or aryl, orR 2 and R 3 are taken together to form (C 2 -C 6)-alkylidene group opt
- -
-
-