41345-72-6Relevant articles and documents
Synthesis of macrocyclic and medium-sized ring thiolactonesviathe ring expansion of lactams
Palate, Kleopas Y.,Epton, Ryan G.,Whitwood, Adrian C.,Lynam, Jason M.,Unsworth, William P.
supporting information, p. 1404 - 1411 (2021/02/27)
A side chain insertion method for the ring expansion of lactams into macrocyclic thiolactones is reported, that can also be incorporated into Successive Ring Expansion (SuRE) sequences. The reactions are less thermodynamically favourable than the analogous lactam- and lactone-forming ring expansion processes (with this notion supported by DFT data), but nonetheless, three complementary protecting group strategies have been developed to enable this challenging transformation to be achieved.
Synthesis, CoMFA analysis, and receptor docking of 3,5-diacyl-2,4- dialkylpyridine derivatives as selective A3 adenosine receptor antagonists
Li, An-Hu,Moro, Stefano,Forsyth, Nancy,Melman, Neli,Ji, Xiao-Duo,Jacobson, Kenneth A.
, p. 706 - 721 (2007/10/03)
3,5-Diacyl-2,4-dialkyl-6-phenylpyridine derivatives have been found to be selective antagonists at both human and rat A3 adenosine receptors (Li et al. J. Med. Chem. 1998, 41, 3186-3201). In the present study, ring- constrained, fluoro, hydroxy, and other derivatives in this series have been synthesized and tested for affinity at adenosine receptors in radioligand binding assays. K(i) values at recombinant human and rat A3 adenosine receptors were determined using [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)- 5'-N-methylcarbamoyladenosine). Selectivity for A3 adenosine receptors was determined vs radioligand binding at rat brain A1 and A(2A) receptors, and structure-activity relationships at various positions of the pyridine ring (the 3- and 5-acyl substituents and the 2- and 4-alkyl substituents) were probed. At the 5-position inclusion of a β-fluoroethyl (7) or a γ- fluoropropyl ester (26) was favorable for human A3 receptor affinity, resulting in K(i) values of 4.2 and 9.7 nM, respectively, while the pentafluoropropyl analogue was clearly less potent at human A3 receptors. At the 2-, 3-, and 4-positions, fluoro or hydroxy substitution failed to enhance potency and selectivity at human A3 receptors. Several analogues were nearly equipotent at rat and human A3 receptors. To further define the pharmacophore conformationally, a lactam, a lactone, and thiolactones were tested in adenosine receptor binding. The most potent analogue in this group was compound 34, in which a thiolactone was formed between 3- and 4-positions and which had a K(i) value of 248 nM at human A3 receptors. Using affinity data and a general pharmacophore model for A3 adenosine receptor antagonists recently proposed, we applied comparative molecular field analysis (CoMFA) to obtain a three dimensional quantitative structure-activity relationship for pyridine derivatives, having good predictability (r2(pred) = 0.873) for compounds in the test set. A rhodopsin-based model of the human As receptor was built, and the pyridine reference ligand 2,3,4,5-tetraethyl-6-phenyl- pyridine-3-thiocarboxylate-5-carboxylate (MRS 1476) was docked in the putative ligand binding site. Interactions between receptor transmembrane domains and the steric and the electrostatic contour plots obtained from the CoMFA analysis were analyzed.
Potent orally active inhibitors of angiotensin-converting enzyme (ACE)
Imaki,Sakuyama,Okada,Toda,Hayashi,Miyamoto,Kawasaki,Okegawa
, p. 2210 - 2214 (2007/10/02)
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