Animal models suggest that the chemokine ligand 2/CC‐chemokine receptor 2 (CCL2/CCR2) axis plays an important role in the development of inflammatory diseases. However, CCR2 antagonists have failed in clinical trials because of a lack of efficacy. We previously described a new approach for the design of CCR2 antagonists by the use of structure–kinetics relationships (SKRs). Herein we report new findings on the structure–affinity relationships (SARs) and SKRs of the reference compound MK‐0483, its diastereomers, and its structural analogues as CCR2 antagonists. The SARs of the 4‐arylpiperidine group suggest that lipophilic hydrogen‐bond‐accepting substituents at the 3‐position are favorable. However, the SKRs suggest that a lipophilic group with a certain size is desired [e.g., 3‐Br: Ki=2.8 nM , residence time (tres)=243 min; 3‐iPr: Ki=3.6 nM , tres=266 min]. Alternatively, additional substituents and further optimization of the molecule, while keeping a carboxylic acid at the 3‐position, can also prolong tres; this was most prominently observed in MK‐0483 (Ki=1.2 nM , tres=724 min) and a close analogue (Ki=7.8 nM ) with a short residence time. 相似文献
The first mono‐iminophosphoranes based on a calix[4]arene skeleton have been synthesised and tested in the arylation of aryl bromides and aryl chlorides. Combining these ligands with [Pd(OAc)2] or [Ni(cod)2] resulted in highly active Suzuki–Miyaura and Kumada–Tamao–Corriu cross‐coupling catalysts, respectively. TOFs up to ca. 4×105 mol(ArBr)⋅mol(M)−1⋅h−1 were obtained in each case. The remarkable activities observed probably arise from the ligands’ ability to form complexes with cavity‐entrapped “MArX” moieties (endo‐complexes), their highly crowded metal environment favouring formation of mono‐ligated intermediates over that of less reactive bis‐ligated ones. Possible supramolecular interactions within the cavity involving the receptor wall and the aromatic substrate may also significantly influence the reaction rates, notably by increasing the proportion of endo‐complexes. 相似文献
A series of 1,2‐ and 1,4‐dihydroquinolines has been successfully prepared. The Pd‐catalyzed intramolecular N‐arylation of Z‐enamines, formally prepared by the Horner–Wadsworth–Emmons olefination, proceeded efficiently to furnish the cyclized products. Depending on the cyclization conditions, substituted 1,4‐dihydroquinolines and further isomerized 1,2‐dihydroquinolines were independently obtained in high yields with an excellent control of isomerization of the double bond.
An efficient synthesis of tetrasubstituted olefins was achieved via a palladium‐catalyzed, chelation‐assisted oxidative Heck arylation protocol from trisubstituted olefins bearing a tether with a directing group in a completely stereo‐ and regioselective manner. The stereo‐ and regioselectivity as well as excellent yields of tetrasubstituted olefins originated from the stabilization of a palladium intermediate by chelation between the palladium center and a directing group. 相似文献
Self‐healing polymer materials have attracted extensive attention and have been explored due to their ability of crack repairing in materials. This paper aims to develop a novel polyurethane‐based material with high self‐healing efficiency and excellent mechanical properties under 80 °C on the basis of reversible Diels–Alder bonds as well as zinc–ligand structure (DA‐ZN‐PU). By integrating DA bonds and zinc–ligand structure, as‐prepared DA‐ZN‐PU samples reach the maximum tensile strength as much as 28.45 MPa. After self‐healing, the tensile strength is 25.85 MPa, leading to the high self‐healing efficiency of 90.8%. In addition, by introducing carbonyl iron powder (CIP), a new polyurethane containing carbonyl iron powder (DA‐ZN‐CIP‐PU) can be achieved, exhibiting microwave‐assisted self‐healing property. And the self‐healing efficiency can be reached to 92.6% in 3 min. Due to high self‐healing efficiency and excellent mechanical properties of the prepared novel polyurethane, it has application attributes in crack repair of functional composite materials. 相似文献
In this study, the kinetics of the thermal decomposition of aminoguanidinium 5,5′‐azobis‐1H‐tetrazolate (AGAT), which is one of the promising fuel candidates of the new gas generating agents for airbags, was investigated. The kinetic model that fits the main decomposition of AGAT was examined, and the activation energy was obtained. The main decomposition of AGAT was a single elementary process according to the result of mass spectrometry. The recommended kinetic model for the main decomposition of AGAT is Avrami–Erofeev equation (n=4). The activation energies for the main decomposition obtained under helium by non‐isothermal analysis and isothermal analysis were 207 and 209 kJ mol−1, respectively. 相似文献
A magnetic nanoparticle‐supported quinuclidine was prepared and evaluated as a recoverable Morita–Baylis–Hillman catalyst. The supported catalyst 2 demonstrated comparable activity with that of DABCO and could be simply recycled with the assistance of an external magnet. The thus recycled catalyst could be reused for 7 times without significant loss of activity. 相似文献
The ytterbium(III) triflate [Yb(OTf)3]‐catalyzed diastereoselective cascade reaction of m‐N,N‐dimethylaminophenyl α,β‐unsaturated carbonyls with cyclopropane 1,1‐diesters under mild reaction conditions afforded highly substituted cis‐ and trans‐tetralins. The reaction of m‐N,N‐dimethylaminophenyl α,β‐unsaturated ketones with cyclopropane 1,1‐diesters provided tetralins with a trans orientation of the 1,4‐substitutents on the cyclohexyl ring; cis‐tetralins were obtained from m‐N,N‐dimethylaminophenyl substituted methylidenemalonates with high diastereoselectivities.
Various 4‐arylnicotinate derivatives were synthesized via a palladium‐catalyzed cascade reaction of N‐(2‐bromoallyl)‐N‐cinnamyltosylamides in a one‐pot procedure in good yields. The reaction involves a domino 5‐exo/3‐exo carbopalladation, ring‐expansion by palladium rearrangement, and an aromatization process. 相似文献