New indole amide derivatives as potent CRTH2 receptor antagonists

Zaghdane, Helmi; Boyd, Michael J.; Colucci, John; Simard, Daniel; Berthelette, Carl; Leblanc, Yves; Wang, Zhaoyin; Houle, Robert; Lévesque, Jean François; Molinaro, Carmela; Hamel, Martine; Stocco, Rino; Sawyer, Nicole; Sillaots, Susan; Gervais, François G.; Gallant, Michel

doi:10.1016/j.bmcl.2011.03.085

Cited by 20 publications

(21 citation statements)

References 22 publications

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“…Ever since the discovery of the nonsteroidal anti‐inflammatory agent indometacin ( 2 , Figure ) to function as a ligand for CRTh2, numerous drug discovery initiatives have been launched aiming to develop orally available CRTh2 antagonists belonging to many different compound classes, currently in the preclinical or early clinical phase . Among these development compounds, medicinal chemistry literature recognizes indol‐1‐yl acetic acids and indol‐3‐yl acetic acids as promising drug candidates . Recently, the 7‐azaindole‐3‐acetic acid NVP‐QAV680 ( 3 , Figure ) was found to be a highly selective compound with low nanomolar functional potency for the in vitro inhibition of CRTh2‐driven human eosinophil and Th2 lymphocyte activation.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a high specific activity methyl sulfone tritium isotopologue of fevipiprant (NVP‐QAW039)

Luu

Goujon

Meisterhans³

et al. 2015

Labelled Comp Radiopharmac

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The synthesis of a triple tritiated isotopologue of the CRTh2 antagonist NVP-QAW039 (fevipiprant) with a specific activity >3 TBq/mmol is described. Key to the high specific activity is the methylation of a bench-stable dimeric disulfide precursor that is in situ reduced to the corresponding thiol monomer and methylated with [(3)H3]MeONos having per se a high specific activity. The high specific activity of the tritiated active pharmaceutical ingredient obtained by a build-up approach is discussed in the light of the specific activity usually to be expected if hydrogen tritium exchange methods were applied.

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Section: Introductionmentioning

confidence: 99%

Synthesis of a high specific activity methyl sulfone tritium isotopologue of fevipiprant (NVP‐QAW039)

Luu

Goujon

Meisterhans³

et al. 2015

Labelled Comp Radiopharmac

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“…a (2) , a (4) , and a (5) parameters are related to the distance + vdW atomic radius for some atoms (C22, C18, O2, C6). The a (1) and a (2) parameters are related to the C22-C18 distance and the van der Waals radius. The C18 atom designates the most remote atom bound to the C22 atom in the R3 position, other than the hydrogen atoms bonded to the carbon atoms.…”

Section: CLmentioning

confidence: 99%

“…Molecular parameters κ j value a (1) C22-C18 distance (Å) 0.0216 a (2) C22-C18 distance (Å)+ vdW radius 0.0564 a (3) Orthogonal distance from the C22 atom to the C1-O1-O3 plane (Å) 0.0243 a (4) Orthogonal distance from the O2 atom to the C1-H6-C12 plane (Å) + vdW radius of O2 atom -0.0139 a (5) Orthogonal distance from the C6 atom to the C1-O1-C12 plane (Å) + vdW radius of C6 atom -0.0713 a (6) The angle of between Cl1-O3-C18 atoms 0.0108 a (7) The angle between the O3-H6-C12 plane and the O2-O4 lines 0.2155 a (8) The angle between the C6-O3-H6 plane and the Cl1-C18 lines 0.1040 a (9) The dihedral angle between the O2-C5-C22-C18 plane -0.0109 Figure 3. Plot of a (1) , a (3) , a (4) , a (5) , a (6) , and a (7) parameters.…”

Section: A (J) Nimentioning

confidence: 99%

“…38 The positive sign, the product of kappa values and parameters, indicates the antipharmacophore shielding group (APS); negative values indicate the auxiliary group (AG). The parameters a (1) , a (2) , a (3) , a (6) , a (7) , and a (8) are APS groups and a (4) and a (5) are AG groups. a (9) belongs to both AG and APS groups because it has positive and negative values in different conformers of the same compound.…”

Section: A (J) Nimentioning

confidence: 99%

“…The CRTh2 receptor (also known as DP2), which is an arachidonic acid metabolite and is released from mast cells, seems to act as a central negotiator for the treatment of asthma and other inflammatory illnesses. 1,2 Allergic diseases and inflammation are commonly related to immunoglobulin E (IgE) production and mast cell activation. 3 Mast cells indirectly participate in asthmatic reactions.…”

Section: Introductionmentioning

confidence: 99%

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4D-QSAR analysis and pharmacophore modeling for alkynylphenoxyacetic acids as CRTh2 (DP2) receptor antagonists

Köprü¹,

Sarıpınar²

2018

Turk J Chem

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In this study, we performed the pharmacophore modeling and 4D-QSAR research of alkynylphenoxyacetic acid analogues as CRTh2 receptor opponent agents by utilizing the electron conformational genetic algorithm method. Quantum chemical calculations and conformational analyses of the compounds were carried out at HF/6-31G* level. Then electron conformational matrices of congruity were prepared for each conformer of each compound, which are represented by electronic and structural properties. As a result of the comparison of the matrices that are called electron conformational submatrices of activity, the pharmacophoric group of the compounds responsible for the activity was found at the determined tolerance intervals. The genetic algorithm and nonlinear least squares regression methods were applied to estimate the conjectural activity and investigate the most reliable molecular identifiers as feature selection from a large parameter pool. The compounds in the dataset were randomly segregated for training (61 compounds) and test sets (25 compounds) for statistical analysis. Validation of the 4D-QSAR model was appraised by the leave-one-out cross-validation technique. For the best model the r 2 training , r 2 test , q 2 , q 2 ext1 , q 2 ext2 , and q 2 ext3 values were found to be 0.

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Synthesis of Tricyclic [1,2‐a]Indoles via Nickel‐Catalyzed Intramolecular Imine‐Alkene Coupling

et al. 2022

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We have developed a method for constructing tricyclic [1,2‐a]indoles via nickel‐catalyzed intramolecular imine‐alkene coupling reactions. This method enables syntheses of 6‐5‐5 and 6‐5‐6 tricyclic [1,2‐a]indoles. The use of NIXantphos or DPPPent as a ligand and 4‐(trifluoromethyl)benzoic acid as a co‐catalyst is crucial for the reaction. The synthetic utility of the method was demonstrated by converting the product into useful indole amines.

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New indole amide derivatives as potent CRTH2 receptor antagonists

Cited by 20 publications

References 22 publications

Synthesis of a high specific activity methyl sulfone tritium isotopologue of fevipiprant (NVP‐QAW039)

Synthesis of a high specific activity methyl sulfone tritium isotopologue of fevipiprant (NVP‐QAW039)

4D-QSAR analysis and pharmacophore modeling for alkynylphenoxyacetic acids as CRTh2 (DP2) receptor antagonists

Synthesis of Tricyclic [1,2‐a]Indoles via Nickel‐Catalyzed Intramolecular Imine‐Alkene Coupling

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