ABSTRACT
G-protein-coupled receptor SUCNR1 (succinate receptor 1 or GPR91) senses the citric cycle intermediate succinate and is implicated in various pathological conditions such as rheumatoid arthritis, liver fibrosis, or obesity. Here, we describe a novel SUCNR1 antagonist scaffold discovered by high-throughput screening. The poor permeation and absorption properties of the most potent compounds, which were zwitterionic in nature, could be improved by the formation of an internal salt bridge, which helped in shielding the two opposite charges and thus also the high polarity of zwitterions with separated charges. The designed compounds containing such a salt bridge reached high oral bioavailability and oral exposure. We believe that this principle could find a broad interest in the medicinal chemistry field as it can be useful not only for the modulation of properties in zwitterionic compounds but also in acidic or basic compounds with poor permeation.
Subject(s)
Benzamides/pharmacology , Phenylacetates/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Animals , Benzamides/chemical synthesis , Benzamides/metabolism , Benzamides/pharmacokinetics , Cell Line , Drug Discovery , Humans , Male , Mice, Inbred C57BL , Phenylacetates/chemical synthesis , Phenylacetates/metabolism , Phenylacetates/pharmacokinetics , Protein Binding , Rats , Receptors, G-Protein-Coupled/metabolism , Static ElectricityABSTRACT
In this review we summarize the most important procedures for the preparation of functionalized organzinc and organomagnesium reagents. In addition, new methods for the preparation of polyfunctional aryl- and heteroaryl zinc- and magnesium compounds, as well as new Pd-catalyzed cross-coupling reactions, are reported herein. Experimental details are given for the most important reactions in the Supporting Information File 1 of this article.
ABSTRACT
Cyclic enol phosphates were magnesiated by a halogen/magnesium exchange reaction or deprotonation using TMP-derived magnesium amide bases. The resulting magnesium reagents react readily with a wide range of electrophiles like allyl bromides and acid chlorides or can be used in Pd-catalyzed cross-coupling reactions. Several optically pure enol phosphates were prepared starting from readily available d-(+)-camphor derivatives.
Subject(s)
Cycloparaffins/chemical synthesis , Halogens/chemistry , Magnesium/chemistry , Phosphates/chemical synthesis , Camphor/chemistry , Catalysis , Cycloparaffins/chemistry , Indicators and Reagents/chemistry , Phosphates/chemistry , Protons , Structure-Activity RelationshipABSTRACT
Alkyl bromides bearing various functional groups are smoothly converted to functionalized alkylzinc reagents by the direct insertion of magnesium in the presence of LiCl and ZnCl(2).
ABSTRACT
The presence of LiCl considerably facilitates the insertion of magnesium into various aromatic and heterocyclic bromides. Several functional groups, such as -OBoc, -OTs, -Cl, -F, -CF(3), -OMe, -NMe(2), and -N(2)NR(2), are well tolerated. The presence of a cyano group leads in some cases to competitive reduction of the organic halide to the corresponding ArH compound. The presence of sensitive groups such as methyl or ethyl ester is tolerated upon in situ trapping of the intermediate magnesium reagent with ZnCl(2). This method can also be applied to the preparation of functionalized benzylic zinc reagents from benzylic chlorides. In the case of di- or tribromoaryl derivatives, directing groups such as -OPiv, -OTs, -N(2)NR(2), or -OAc orient the zinc insertion (Zn/LiCl) to the ortho-position, while the reaction with Mg/LiCl or Mg/LiCl/ZnCl(2) leads to regioselective insertion into the para-carbon-bromine bond. Large-scale experiments (20-100 mmol) for all of the metalation procedures are described.
ABSTRACT
A full functionalization of all four positions of the thiophene ring was achieved. Starting from readily available 2,5-dichlorothiophene, successive magnesiations of the 3- and 4-positions using TMPMgCl x LiCl furnish, after trapping with various electrophiles, 3,4-difunctionalized dichlorothiophenes. Subsequent dechlorination and metalation or magnesium insertion into the C-Cl bond provides fully functionalized thiophenes in high yields. An application to the synthesis of a thiophene analogue of Atorvastatin (Lipitor) is reported.
Subject(s)
Thiophenes/chemical synthesis , Carbon/chemistry , Catalysis , Microwaves , Palladium/chemistry , Stereoisomerism , Substrate Specificity , Thiophenes/chemistryABSTRACT
Benzylic zinc chlorides bearing various functional groups are smoothly prepared by the direct insertion of magnesium into benzylic chlorides in the presence of LiCl and ZnCl(2).
