- Structure-Guided Modification of Heterocyclic Antagonists of the P2Y14 Receptor
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The P2Y14 receptor (P2Y14R) mediates inflammatory activity by activating neutrophil motility, but few classes of antagonists are known. We have explored the structure-activity relationship of a 3-(4-phenyl-1H-1,2,3-triazol-1-yl)-5-(aryl)benzoic acid antagonist scaffold, assisted by docking and molecular dynamics (MD) simulation at a P2Y14R homology model. A computational pipeline using the High Throughput MD Python environment guided the analogue design. Selection of candidates was based upon ligand-protein shape and complementarity and the persistence of ligand-protein interactions over time. Predictions of a favorable substitution of a 5-phenyl group with thiophene and an insertion of a three-methylene spacer between the 5-aromatic and alkyl amino moieties were largely consistent with empirical results. The substitution of a key carboxylate group on the core phenyl ring with tetrazole or truncation of the 5-aryl group reduced affinity. The most potent antagonists, using a fluorescent assay, were a primary 3-aminopropyl congener 20 (MRS4458) and phenyl p-carboxamide 30 (MRS4478).
- Yu, Jinha,Ciancetta, Antonella,Dudas, Steven,Duca, Sierra,Lottermoser, Justine,Jacobson, Kenneth A.
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supporting information
p. 4860 - 4882
(2018/06/20)
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- IMIDAZO [1,5-A]PYRIMIDINYL CARBOXAMIDE COMPOUNDS AND THEIR USE IN THE TREATMENT OF MEDICAL DISORDERS
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The invention provides substituted imidazo[1,5-a]pyrimidinyl carboxamide and related organic compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat medical disorders, e.g., Gaucher disease, Parkinson's disease, Lewy body disease, dementia, or multiple system atrophy, in a patient. Exemplary substituted imidazo[1,5-a]pyrimidinyl carboxamide compounds described herein include substituted 2-heterocyclyl-4-alkyl-imidazo[1,5-a]pyrirnidine-8-carboxamide compounds and variants thereof.
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Paragraph 00694
(2017/11/04)
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- T-BuXPhos: A highly efficient ligand for Buchwald-Hartwig coupling in water
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An efficient and versatile 'green' catalytic system for the Buchwald-Hartwig cross-coupling reaction in water is reported. In an aqueous micellar medium, the combination of t-BuXPhos with [(cinnamyl)PdCl]2 showed excellent performance for coupling arylbromides or chlorides with a large set of amines, amides, ureas and carbamates. The method is functional-group tolerant, proceeds smoothly (30 to 50 °C) and provides rapid access to the target compounds in good to excellent isolated yields. When applied to the synthesis of a known NaV1.8 modulator, this method led to a significant improvement of the E-factor in comparison with classical organic synthesis. the Partner Organisations 2014.
- Wagner, Patrick,Bollenbach, Maud,Doebelin, Christelle,Bihel, Frederic,Bourguignon, Jean-Jacques,Salome, Christophe,Schmitt, Martine
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supporting information
p. 4170 - 4178
(2014/09/29)
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- BENZIMIDAZOLE CANNABINOID AGONISTS BEARING A SUBSTITUTED HETEROCYCLIC GROUP
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The present invention is related to novel benzimidazole compounds of formula (I) having cannabinoid receptor agonistic properties, pharmaceutical compositions comprising these compounds, chemical processes for preparing these compounds and their use in the treatment of diseases linked to the mediation of the cannabinoid receptors in animals, in particular humans.
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Paragraph 0174; 0175
(2014/01/07)
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- BENZIMIDAZOLE CANNABINOID AGONISTS BEARING A SUBSTITUTED HETEROCYCLIC GROUP
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The present invention is related to novel benzimidazole compounds of formula (I) having cannabinoid receptor agonistic properties, pharmaceutical compositions comprising these compounds, chemical processes for preparing these compounds and their use in the treatment of diseases linked to the mediation of the cannabinoid receptors in animals, in particular humans.
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Page/Page column 30
(2008/06/13)
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- New insertion reactions of some carbenoids into amide- and sulfonamide-NH bonds
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In the presence of catalytic amounts of Rh2(OAc)4 in toluene, dimethyl diazomalonate (1) decomposed with evolution of N2 to form a carbenoid of type 8 which reacted with carboxamides 2 and toluenesulfonamide (4) to give 2-(acylamino)- and 2-(sulfonylamino)malonates 3 and 5, respectively. In an analogous reaction, α-diazo ketone 6 and 4 yielded N-(2-oxo-1,2-diphenylethyl)toluenesulfonamide (7).
- Mloston,Celeda,Swiatek,Kaegi,Heimgartner
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p. 1907 - 1914
(2007/10/03)
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- Chemistry of furans: Part VIII - Synthesis of 5-dialkylamino-2-furanamides and furanopeptides
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The synthesis of 5-dialkylamino-furanamides by the nucleophilic displacement of bromine on 5-bromo-2-furanamides with pyrrolidine, piperidine and morpholine is described.Several other primary and secondary amines as well as nucleophiles such as sodio amid
- Rai, Usha Kumari,Mishra, S K,Shanker, Brija,Singh, Sujan,Rao, R Balaji
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p. 618 - 623
(2007/10/02)
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- Chemistry of Furans: Part VI - Synthesis of 5-Amino-2-furanamides
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5-Amino-2-furanamides (II) have been synthesised by the nucleophilic displacement of bromine in 5-bromo-2-furanamides by piperidine, pyrrolidine and morpholine.
- Rai, Usha Kumari,Shanker, Birja,Singh, Sujan,Rao, R. Balaji
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p. 674 - 675
(2007/10/02)
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- Hypoglycemic 5-substituted oxazolidine-2,4-diones
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Hypoglycemic 5-furyl and 5-thienyl derivatives of oxazolidine-2,4-dione and the pharmaceutically-acceptable salts thereof; certain 3-acylated derivatives thereof; and intermediates useful in the preparation of said compounds.
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