The resolution of inflammation (RoI), once believed to be a passive process, has lately been shown to be an active and delicately orchestrated process. During the resolution phase of acute inflammation, novel mediators, including lipoxins and resolvins, which are members of the specialized pro-resolving mediators of inflammation, are produced. FPR2/ALXR, a receptor modulated by some of these lipids as well as by peptides (e.g., annexin A1), has been shown to be one of the receptors involved in the RoI. The aim of this perspective is to present the concept of the RoI from a medicinal chemistry point of view and to highlight the effort of the research community to discover and develop antiinflammatory/pro-resolution small molecules to orchestrate inflammation by activation of FPR2/ALXR.
Chiral Lewis acid catalysis has emerged as one of the premiere method to control stereochemistry. Much effort has gone into the design of superior ligands with increasing steric extension to shield distant reactive sites. We report here an alternative and complementary approach based on a "chiral relay". This strategy focuses on the improved design of achiral templates which may relay and amplify the stereochemistry from ligands. The essence of this strategy is that the chiral Lewis acid would effectively convert an achiral template into a chiral non-racemic template. This approach combines the advantages of enantioselective catalysis (substoichiometric amount of the chiral inducer) with the ones of chiral auxiliary control (efficient and predictable stereocontrol).
Enantioselective total syntheses of briarellin E (4) and briarellin F (5) have been achieved starting with (S)-(+)-carvone and (S)-(-)-glycidol. These total syntheses are the first of briarellin diterpenes. The central step in these syntheses is acid-promoted condensation of cyclohexadienyl diol 15 and (Z)-alpha,beta-unsaturated aldehyde 16 to form, with complete stereocontrol, the hexahydroisobenzofuran core and six stereocenters of these coral metabolites. These syntheses also feature stereospecific photolytic deformylation of beta,gamma-unsaturated aldehyde 17 to remove the extraneous carbon introduced in the Prins-pinacol step, chemo- and stereoselective hydroxyl-directed epoxidation of dienyl alcohol 18 to incorporate the C3 oxygen stereocenter, regio- and stereoselective rearrangement of epoxy ester 19 to install the C4 oxygen substituent, efficient dehydrative cyclization of a 1,6-diol intermediate to form the oxepane ring, and diastereoselective Nozaki-Hiyama-Kishi cyclization of vinyl iodide aldehyde 25 to forge the oxacyclononane ring and the C6 hydroxyl stereocenter. These total syntheses establish the absolute configurations of 4 and 5, define a concise strategy for the total synthesis of briarellin diterpenes, and provide additional illustrations of the uncommon utility of pinacol-terminated cationic cyclizations for stereocontrolled synthesis of complex oxacyclic natural products.
Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.
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