AZ465 is a novel selective transient receptor potential cation channel, member A1 (TRPA1) antagonist identified during a focused drug discovery effort. In vitro, AZ465 fully inhibits activation by zinc, O-chlorobenzylidene malononitrile (CS), or cinnamaldehyde of the human TRPA1 channel heterologously expressed in human embryonic kidney cells. Our data using patch-clamp recordings and mouse/human TRPA1 chimeras suggest that AZ465 binds reversibly in the pore region of the human TRPA1 channel. Finally, in an ex vivo model measuring TRPA1 agonist-stimulated release of neuropeptides from human dental pulp biopsies, AZD465 was able to block 50%-60% of CS-induced calcitonin gene-related peptide release, confirming that AZ465 inhibits the native human TRPA1 channel in neuronal tissue.

The pharmacology and regulation of Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel activity is intricate due to the physiological function as an integrator of multiple chemical, mechanical, and temperature stimuli as well as differences in species pharmacology. In this study, we describe and compare the current inhibition efficacy of human TRPA1 on three different TRPA1 antagonists. We used a homology model of TRPA1 based on Kv1.2 to select pore vestibule residues available for interaction with ligands entering the vestibule. Site-directed mutation constructs were expressed in Xenopus oocytes and their functionality and pharmacology assessed to support and improve our homology model. Based on the functional pharmacology results we propose an antagonist-binding site in the vestibule of the TRPA1 ion channel. We use the results to describe the proposed intravestibular ligand-binding site in TRPA1 in detail. Based on the single site substitutions, we designed a human TRPA1 receptor by substituting several residues in the vestibule and adjacent regions from the rat receptor to address and explain observed species pharmacology differences. In parallel, the lack of effect on HC-030031 inhibition by the vestibule substitutions suggests that this molecule interacts with TRPA1 via a binding site not situated in the vestibule.

A series of potent antagonists of the ion channel transient receptor potential A1 (TRPA1) was developed by modifying lead structure 16 that was discovered by high-throughput screening. Based on lead compound 16, a SAR was established, showing a narrow region at the nitro-aromatic R1 moiety and at the warhead, while the R2 side had a much wider scope including ureas and carbamates. Compound 16 inhibits Ca2+-activated TRPA1 currents reversibly in whole cell patch clamp experiments, indicating that under in vivo conditions, it does not react covalently, despite its potentially electrophilic ketone.

Tetrazolo[1,5-a]pyrimidines are capable of serving as masked azides in copper-catalyzed Huisgen cyclization with a variety of terminal alkynes, providing a simple protocol for the generation of novel 4'-substituted 2-(1',2',3'-triazol-l'yl)pyrimidines.

Acid-mediated condensation between benzoylpyruvates and various dinucleophiles in alcoholic solvent furnished the heterocyclic imprint in moderate to good yield. Combining a range of symmetric as well as nonsymmetric nitrogen/nitrogen or nitrogen/carbon centered dinucleophiles resulted in excellent regioselectivity. gamma-Difunctionalized fused pyrimidines, pyridazines, and pyridines were produced in this manner. The protocol was designed to obviate chromatographic purification.

A method is introduced for performing reagent selection for chemical library design based on topological (2D) pharmacophore fingerprints. Optimal reagent selection is achieved by optimizing the Shannon entropy of the 2D pharmacophore distribution for the reagent set. The method, termed ProSAR, is therefore expected to enumerate compounds that could serve as a good starting point for deriving a structure activity relationship (SAR) in combinatorial library design. This methodology is exemplified by library design examples where the active compounds were already known. The results show that most of the pharmacophores on the substituents for the active compounds are covered by the designed library. This strategy is further expanded to include product property profiles for aqueous solubility, hERG risk assessment, etc. in the optimization process so that the reagent pharmacophore diversity and the product property profile are optimized simultaneously via a genetic algorithm. This strategy is applied to a two-dimensional library design example and compared with libraries designed by a diversity based strategy which minimizes the average ensemble Tanimoto similarity. Our results show that by using the PSAR methodology, libraries can be designed with simultaneously good pharmacophore coverage and product property profile.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The present review covers the utility of benzoylpyruvates as it vehicle for the preparation of highly functionalized heterocycles. Regio- and chemoselective features are discussed with reference to the application of different nucleophilic species. In this context, the preparation of such rings as pyrazoles, isoxazoles, primidines, and pyridines are presented. As the means to establish it distinct functional pattern, the rendered strategy can be seen as an alternative to cross-coupling protocols.

Two new C9 protecting groups for the anomeric position of carbohydrates are reported. Methods both for their introduction and removal are described. The C9-protected compounds are much less polar than the corresponding allyl protected analogues. The new protecting group chemistry has been used to prepare compound 17 en route to a disaccharide analogue of the antibiotic moenomycin A.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The novel linker methyl 2-(4-methoxycarbonylbutyldimethylsily)ethanol (3) was synthesized in 58% overall yield over four steps, starting from 2-(hexenyldimethylsilyl)ethanol. Galactopyranosylation of 3 and coupling of the resulting linker galactoside to aminomethylated polystyrene resin gave a material that could be efficiently de-O-benzoylated as well as O-propionylated. Treatment of the resin with acetic or propionic anhydride in the presence of BF3·OEt2 gave the corresponding l-O-propionyl or -acetyl galactopyranoses.

The novel linker 4 was synthesized in three steps from hex-5-enyldimethylchlorosilane and glycosylated with 2,3,4,6-tetra-O-benzoyl-α-D-galactopyranosyl trichloroacetimidate to give the corresponding linker β-glycoside 5 (77%). Treatment of 5 with acetic anhydride and BF3·OEt2 gave 1-O-acetyl-2,3,4,6-tetra-O-benzoyl-β-D-galactose (∼90%), devoid of the α-anomer.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Two new C-9 protecting groups for the anomeric position of carbohydrates are reported. Methods both for their introduction and removal are described. The C-9-protected compounds are much less polar than the corresponding allyl protected analogues.

The stimulation of Orobanche crenata seed germination by (+)-strigol and a series of structurally related compounds differing from (+)-strigol in constitution and/or configuration is described. Both constitution and configuration of the stimulants influence the biological activity. The absolute configuration at C-2′ (strigol numbering) seems to be of special importance.

Configurational assignment at C-2' of several strigol analogues by (i) X-ray analysis, (ii) chemical correlation, and (iii) circular dichroism is described.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.