72016-68-3Relevant academic research and scientific papers
Indole compounds with: N-ethyl morpholine moieties as CB2 receptor agonists for anti-inflammatory management of pain: Synthesis and biological evaluation
Ji, Jing,Li, Jiaojiao,Li, Zhengfu,Xu, Ruibo
supporting information, p. 1935 - 1947 (2019/11/20)
The CB2 receptor plays a crucial role in analgesia and anti-inflammation. To develop novel CB2 agonists with high efficacy and selectivity, a series of indole derivatives with N-ethyl morpholine moieties (compounds 1-56) were designed, synthesized and biologically evaluated. Compounds 1, 2, 3, 46 and 53 exhibited high CB2 receptor affinity at low nanomolar concentrations and good receptor selectivity (EC50(CB1)/EC50(CB2) greater than 1000). The most active compound, compound 2, was more potent than the standard drug GW405833 for in vitro agonistic action on the CB2 receptor. More importantly, in a rat model for CFA-induced inflammatory hyperalgesia, compound 2 had a potent anti-inflammatory pain effect within 12 hours after administration. At the 1 h time point, compound 2 had a dose-dependent reversal for hyperalgesia with an estimated ED50 value of 1.097 mg kg-1. Moreover, compound 2 significantly suppressed the pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in CFA-induced lesions. These protective effects of compound 2 on inflammatory pain were superior to those of GW405833, suggesting that compound 2 may be a promising therapeutic drug that needs further validation.
Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity
De Vita, Elena,Schüler, Peter,Lovell, Scott,Lohbeck, Jasmin,Kullmann, Sven,Rabinovich, Eitan,Sananes, Amiram,He?ling, Bernd,Hamon, Veronique,Papo, Niv,Hess, Jochen,Tate, Edward W.,Gunkel, Nikolas,Miller, Aubry K.
supporting information, p. 8859 - 8874 (2018/10/09)
Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins (KLKs). Many KLKs are investigated as potential biomarkers for cancer as well as therapeutic drug targets for a number of pathologies. KLK6, in particular, has been implicated in neurodegenerative diseases and cancer, but target validation has been hampered by a lack of selective inhibitors. This work introduces a class of depsipeptidic KLK6 inhibitors, discovered via high-throughput screening, which were found to function as substrate mimics that transiently acylate the catalytic serine of KLK6. Detailed structure-activity relationship studies, aided by in silico modeling, uncovered strict structural requirements for potency, stability, and acyl-enzyme complex half-life. An optimized scaffold, DKFZ-251, demonstrated good selectivity for KLK6 compared to other KLKs, and on-target activity in a cellular assay. Moreover, DKFZ-633, an inhibitor-derived activity-based probe, could be used to pull down active endogenous KLK6.
Discovery and refinement of a new structural class of potent peptide deformylase inhibitors
Boularot, Adrien,Giglione, Carmela,Petit, Sylvain,Duroc, Yann,De Sousa, Rodolphe Alves,Larue, Valéry,Cresteil, Thierry,Dardel, Frédéric,Artaud, Isabelle,Meinnel, Thierry
, p. 10 - 20 (2007/10/03)
New classes of antibiotics are urgently needed to counter increasing levels of pathogen resistance. Peptide deformylase (PDF) was originally selected as a specific bacterial target, but a human homologue, the inhibition of which causes cell death, was rec
Inhibition of cytosolic phospholipase A2α: Hit to lead optimization
McKew, John C.,Foley, Megan A.,Thakker, Paresh,Behnke, Mark L.,Lovering, Frank E.,Sum, Fuk-Wah,Tam, Steve,Wu, Kun,Shen, Marina W. H.,Zhang, Wen,Gonzalez, Mario,Liu, Shanghao,Mahadevan, Anu,Sard, Howard,Khor, Soo Peang,Clark, James D.
, p. 135 - 158 (2007/10/03)
Compound 1 was previously reported to be a potent inhibitor of cPLA 2α in both artificial monomeric substrate and cell-based assays. However, 1 was inactive in whole blood assays previously used to characterize cyclooxygenase and lipoxygenase inhibitors. The IC50 of 1 increased dramatically with cell number or lipid/detergent concentration. In an attempt to insert an electrophilic ketone between the indole and benzole acid moieties, we discovered that increasing the distance between the two moieties gave a compound with activity in the GLU (7-hydroxycoumarinyl-γ- linolenate) micelle assay, which contains lipid and detergent. Extensive structure-activity relationship work around this lead identified a potent pharmacophore for cPLA2α inhibition. The IC50s between the GLU micelle and rat whole blood assays correlated highly. No correlation was found for other parameters, including lipophilicity or acidity of the required acid functionality. Compounds 25, 39, and 94 emerged as potent, selective inhibitors of cPLA2α and represent well-validated starting points for further optimization.
Hypoglycemic imidazoline compounds
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Page/Page column 18, (2010/02/05)
This invention relates to certain novel imidazoline compounds and analogues thereof, to their use for the treatment of diabetes, diabetic complications, metabolic disorders, or related diseases where impaired glucose disposal is present, to pharmaceutical compositions comprising them, and to processes for their preparation.
Hypoglycemic imidazoline compounds
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Page 29, (2010/11/29)
This invention relates to certain novel imidazoline compounds and analogues thereof, to their use for the treatment of diabetes, diabetic complications, metabolic disorders, or related diseases where impaired glucose disposal is present, to pharmaceutical compositions comprising them, and to processes for their preparation. The compounds have the following formula: whereinX is -O-, -S-, or -NR5-;R5 is hydrogen, C1-8 alkyl, or an amino protecting group;R1, R1', R2, and R3 are independently hydrogen or C1-8 alkyl;R1 and R2 optionally together form a bond and R1' and R3 are independently hydrogen or C1-8 alkyl;R1 and R2 optionally combine together with the carbon atoms to which they are attached form a C3-7 carbocyclic ring and R1' and R3 are independently hydrogen or C1-8 alkyl;R1 and R1' together with the carbon atom to which they are attached optionally combine to form a C3-7 spirocarbocyclic ring and R2 and R3 are independently hydrogen or C1-8 alkyl;R2 and R3 together with the carbon atom to which they are attached optionally combine to form a C3.7 spirocarbocyclic and R1 and R1' are independently hydrogen or C1-8 alkyl;n is 0, 1, or 2;m is 1 or2; 2;m' is 0, 1, or 2;q' is 0,1,2,3,4, or 5;R4 isY is -O-, -S-, or -NR8-;Y' is -O- or -S-;R6 and R7 are independently hydrogen, C1-8 alkyl, C3-7 cycloalkyl, C1-8 alkoxy, C1-8 alkylthio, halo C1-8 alkylthio, C1-8 alkylsulfinyl, C1-8 alkylsulfonyl. C3-7 cycloalkoxy, aryl-C1-8 alkoxy, halo, halo-C1-8 alkyl, halo-C1-8 alkoxy, nitro, -NR10R11, -CONR10R11, aryl C1-8 alkyl, optionally substituted heterocyclyl, optionally substituted phenyl, optionally substituted naphthyl, optionally halo substituted acylamino, cyano, hydroxy, COR12, halo C1-8 alkylsulfinyl, or halo C1-8 alkylsulfonyl, or alkoxyalkyl of the formulaCH3(CH2)p-O-(CH2)q-O-; wherep is 0, 1, 2, 3, or 4; andq is 1, 2, 3, 4, or 5;R12 is C1-8 alkyl or optionally substituted phenyl;R8 is hydrogen, C1-8 alkyl, halo-C1-8 alkyl, optionally substituted phenyl, optionally substituted heterocyclyl, COO C1-8 alkyl, optionally substituted COaryl, COC1-8 alkyl, SO2C1-8 alkyl, optionally substituted SO2 aryl, optionally substituted phenyl-C1-8 alkyl, CH3(CH2)p-O-(CH2)q-O-;R9 is hydrogen, halo, C1-8 alkyl, halo C1-8 alkyl, C1-8 alkylthio, halo C1-8 alkylthio, C3-7 cycloalkylthio, optionally substituted arylthio or heteroarylthio, C1-8 alkoxy, C3-8 cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, or optionally substituted aryl or heteroaryl, C3-7 cycloalkyl, halo C3-7 cycloalkyl, C3-7 cycloalkenyl, cyano, COOR10,CONR10R11 or NR10R11,C2-6 alkenyl, optionally substituted heterocyclyl, optionally substituted aryl C1-8 alkyl, optionally substituted heteroaryl C1-8 alkyl in which the alkyl group can be substituted by hydroxy, or C1-8 alkyl substituted by hydroxy,R10 and R11 are independently hydrogen, C1-8 alkyl, optionally substituted aryl C1-8 alkyl, optionally substituted phenyl, or R10 and R11 together with the nitrogen atom to which they are attached may combine to form a ring with up to six carbon atoms which optionally may be substituted with up to two C1-8 alkyl groups or one carbon atom may be replaced by oxygen or sulfur;R14 and R16 are independently hydrogen, halo, C1-8 alkyl, C3-7 cycloalkyl, C3-7 cycloalkoxy, C3-7 cycloalkylC1-8 alkoxy, halo-C1-8 alkyl, halo-C1-8 alkoxy, C1-8 alkoxy, carbo(C1-8)alkoxy, optionally substituted aryl, or optionally substituted heteroaryl;R15 and R17 are independently hydrogen, halo, C1-8 alkoxy, C3-7-cycloalkyl, C3-7 cycloalkylC1-8 alkoxy, C1-8 alkyl, C3-7 cycloalkoxy, hydroxy, halo C1-8 alkoxy, carbo(C1-8)alkoxy, optionally substituted phenyl, optionally substituted phenyl-C1-8 alkyl, optionally substituted phenyloxy, optionally substituted phenyl-C1-8 alkoxy, (tetrahydropyran-2-yl)methoxy, C1-8 alkyl-S(O)m-, optionally substituted aryl-C1-8 alkyl-S(O)m·-, CH3(CH2)p-Z1-(CH2)q-Z2-, or Z3-(CH2)q'-Z2-;Z1 and Z2 are independently abond, O, S, SO, SO2, sulphoximino, or NR10; andZ3 is hydroxy, protected hydroxy, NR10 R11, protected amino, SH or protected SH; ???provided that when R1, R1', R2 and R3 are all hydrogen; n is 0; R4 is naphthyl; and R14 R15 and R16, or R15, R16 and R17 are all hydrogen, then R17 or R14, respectively, is other than halo, methoxy, or C1-6 alkyl. ???or a pharmaceutically acceptable salt or ester thereof.
Thiazole analogues of the NSAID indomethacin as selective COX-2 inhibitors
Woods, Keith W.,McCroskey, Richard W.,Michaelides, Michael R.,Wada, Carol K.,Hulkower, Keren I.,Bell, Randy L.
, p. 1325 - 1328 (2007/10/03)
The carboxyl group of the NSAID indomethacin was replaced with a variety of substituted thiazoles to obtain a series of potent, selective inhibitors of COX-2. Additional substitutions were made at the 1-position and 5-position of the indole of indomethacin.
1H-INDOLE-3-ACETIC ACID HYDRAZIDE SPLA2 INHIBITORS
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, (2008/06/13)
A class of novel 1H-indole-3-acetic acid hydrazides is disclosed together with the use of such indole compounds for inhibiting sPLA2 mediated release of fatty acids (e.g., arachidonic acid) for treatment of conditions such as septic shock
Indole inhibitors of human nonpancreatic secretory phospholipase A2. 1. Indole-3-acetamides
Dillard, Robert D.,Bach, Nicholas J.,Draheim, Susan E.,Berry, Dennis R.,Carlson, Donald G.,Chirgadze, Nickolay Y.,Clawson, David K.,Hartley, Lawrence W.,Johnson, Lea M.,Jones, Noel D.,McKinney, Emma R.,Mihelich, Edward D.,Olkowski, Jennifer L.,Schevitz, Richard W.,Smith, Amy C.,Snyder, David W.,Sommers, Cynthia D.,Wery, Jean-Pierre
, p. 5119 - 5136 (2007/10/03)
Phospholipases (PLAs) produce rate-limiting precursors in the biosynthesis of various types of biologically active lipids involved in inflammatory processes. Increased levels of human nonpancreatic secretory phospholipase A2 (hnps-PLA2) have been detected in several pathological conditions. An inhibitor of this enzyme could have therapeutic utility. A broad screening program was carried out to identify chemical structures which could inhibit hnps-PLA2. One of the lead compounds generated by the screening program was 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (13a). We describe the syntheses, structure-activity relationships, and pharmacological activities of a series of indole-3-acetamides and related compounds derived from this lead. This SAR was undertaken with the aid of X- ray crystal structures of complexes between the inhibitors and hnps-PLA2 which were of great value in directing the SAR.
N-benzyl-3-indoleacetic acids as antiinflammatory drugs
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, (2008/06/13)
The invention encompasses the novel compound of Formula I as well as a method of treating inflammation and, in particular, cyclooxygenase-2 mediated diseases comprising administration to a patient in need of such treatment of a non-toxic therapeutically e
