Brain penetrant liver X receptor (LXR) modulators based on a 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole core.

Liver X receptor (LXR) agonists have been reported to lower brain amyloid beta (Aß) and thus to have potential for the treatment of Alzheimer's disease. Structure and property based design led to the discovery of a series of orally bioavailable, brain penetrant LXR agonists. Oral administration of compound 18 to rats resulted in significant upregulation of the expression of the LXR target gene ABCA1 in brain tissue, but no significant effect on Aß levels was detected.

Discovery of a Novel, Orally Efficacious Liver X Receptor (LXR) ß Agonist.

This article describes the application of Contour to the design and discovery of a novel, potent, orally efficacious liver X receptor ß (LXRß) agonist (17). Contour technology is a structure-based drug design platform that generates molecules using a context perceptive growth algorithm guided by a contact sensitive scoring function. The growth engine uses binding site perception and programmable growth capability to create drug-like molecules by assembling fragments that naturally complement hydrophilic and hydrophobic features of the protein binding site. Starting with a crystal structure of LXRß and a docked 2-(methylsulfonyl)benzyl alcohol fragment (6), Contour was used to design agonists containing a piperazine core. Compound 17 binds to LXRß with high affinity and to LXRα to a lesser extent, and induces the expression of LXR target genes in vitro and in vivo. This molecule served as a starting point for further optimization and generation of a candidate which is currently in human clinical trials for treating atopic dermatitis.

Identification of spirooxindole and dibenzoxazepine motifs as potent mineralocorticoid receptor antagonists.

Mineralocorticoid receptor (MR) antagonists continue to be a prevalent area of research in the pharmaceutical industry. Herein we report the discovery of various spirooxindole and dibenzoxazepine constructs as potent MR antagonists. SAR analysis of our spirooxindole hit led to highly potent compounds containing polar solubilizing groups, which interact with the helix-11 region of the MR ligand binding domain (LBD). Various dibenzoxazepine moieties were also prepared in an effort to replace a known dibenzoxepane system which interacts with the hydrophobic region of the MR LBD. In addition, an X-ray crystal structure was obtained from a highly potent compound which was shown to exhibit both partial agonist and antagonist modes of action against MR.

Expanding the pleuromutilin class of antibiotics by de novo chemical synthesis.

New pleuromutilin-like compounds were synthesized in approximately 11 steps from 3-allylcyclopent-2-enone by a strategy featuring sequential carbonyl addition reactions. Several analogs possessing the C14 tiamulin ester side chain displayed activity in a Mycobacterium tuberculosis mc(2)7000 assay. The results described herein provide a basis for further efforts to expand the structural and stereochemical diversity of the pleuromutilin class of bacterial protein synthesis inhibitors through advances in chemical synthesis.

A concise synthesis of the molecular framework of pleuromutilin.

Two syntheses of the tricyclic carbon skeleton of pleuromutilin are reported. Diastereoselective 1,4-conjugate additions were used to elaborate bicyclic precursors at an early stage of each route, while ring-forming olefin metatheses were executed to complete the pleuromutilin carbon framework. The congeners prepared are appropriately functionalized to enable access to diverse pleuromutilin analogues.

Spirodiepoxide strategy to the C ring of pectenotoxin 4: synthesis of the C1-C19 sector.

The synthesis of a C1-C19 precursor to pectenotoxin 4 is presented. The strategy employed the functionalized allene shown. Key features include: olefin metathesis of two simple fragments to prepare the left portion of the allene-precursor, diastereoselective propargylation of an epoxy aldehyde to form the right portion, use of the DMDO-stable m-fluorobenzyl ether, and an allene spirodiepoxidation/C-ring formation cascade.

A spirodiepoxide-based strategy to the A-B ring system of pectenotoxin 4.

[reaction: see text] A synthesis of a pectenotoxin 4 C1-C15 segment is reported. Suitable C1-C7 and C8-C15 segments were prepared, coupled, converted to I and the C3-hydroxy variant, and then cyclized. Key findings include the stereoselective conversion of the allene to the corresponding spirodiepoxide, oxidative cleavage of the p-methoxybenzyl ether, and cyclization of the spirodiepoxide to spiroketal II.

Spirodiepoxides in total synthesis: epoxomicin.

The first use of the spirodiepoxide functional group in total synthesis, a study culminating in an efficient synthesis of the potent proteasome inhibitor epoxomicin, is described. Spirodiepoxides derived from allenes by oxidation are shown to give syn disubstituted ketones and their derivatives, including ortho ester, oxazoline, azido epoxide, as well as sulfonamide-, amide-, and azide-containing hydroxy ketones.