Detailed pharmacokinetic characterization of advanced topical acyclovir formulations with IVPT and in vivo Open Flow Microperfusion.

Successful treatment of herpes simplex viruses is currently limited by a lack of effective topical drugs. Commonly used topical acyclovir products only reduce the duration of lesions by a few days. Optimizing topical formulations to achieve an enhanced acyclovir solubility and penetration could increase the efficacy of topically applied acyclovir, but new formulations need to show reliable acyclovir delivery into at least the epidermis/dermis and need to provide sustained acyclovir release for extended time periods. The aim of this study was to compare pharmacokinetic data from in vitro permeation testing (IVPT) and preclinical dermal open flow microperfusion (dOFM) experiments regarding the penetration behavior of different acyclovir formulations relative to the reference product Zovirax® 5% cream. Four test formulations that delivered the best penetration data in IVPT were further tested using continuous dOFM in vivo dermal sampling. The use of dOFM identified one of the four tested formulations to perform significantly better than the other three tested formulations and the reference product. In vivo dOFM data showed differences in the dermal acyclovir concentration that had not been detected by using IVPT. Improved acyclovir delivery to the dermis was likely achieved by the new formulation that uses a much lower drug load compared to the reference product. This optimized formulation was able to achieve a dermal concentration similar to oral application and can thus provide the opportunity of more efficacious topical HSV-1 treatment with less side effects than oral systemic treatment.

An enyne cycloisomerization approach to the triple reuptake inhibitor GSK1360707F.

The triple reuptake inhibitor GSK1360707F was synthesized via an efficient and scalable route that features an enyne cycloisomerization reaction catalyzed by either Pt(II) or Au(I). Key aspects of this work such as the choice of the nitrogen protecting group and initial enantioselectivity studies are discussed.

Asymmetric synthesis of an N-acylpyrrolidine for inhibition of HCV polymerase.

A practical asymmetric synthesis of a highly substituted N-acylpyrrolidine on multi-kilogram scale is described. The key step in the construction of the three stereocenters is a [3+2] cycloaddition of methyl acrylate and an imino ester prepared from l-leucine t-butyl ester hydrochloride and 2-thiazolecarboxaldehyde. The cycloaddition features novel asymmetric catalysis via a complex of silver acetate and a cinchona alkaloid, particularly hydroquinine, with complete diastereomeric control and up to 87% enantiomeric control. The alkaloid serves as a ligand as well as a base for the formation of the azomethine ylide or 1,3-dipole. Experiments have shown that the hydroxyl group of hydroquinine is a critical element for the enantioselectivities observed. The cycloaddition methodology is also applicable to methylvinyl ketone, providing access to either alpha- or beta-epimers of 4-acetylpyrrolidine depending on the reaction conditions utilized. The synthesis also highlights an efficient N-acylation, selective O- versus N-methylation, and a unique ester reduction with NaBH4-MeOH catalyzed by NaB(OAc)3H that not only achieves excellent chemoselectivity but also avoids formation of the undesired but thermodynamically favored epimer. The highly functionalized target is synthesized in seven linear steps from l-leucine t-butyl ester hydrochloride with all three isolated intermediates being highly crystalline.

An efficient synthesis of a potent PPARpan agonist.

An efficient synthesis of 2-{4-[({4-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)thio]phenoxy}-2-methylpropanoic acid (1), a potent PPARpan agonist, is described. The seven-step synthesis, which afforded 1 in 30% overall yield, includes a highly regioselective carbon-sulfur bond formation via coupling of a bishydroxymethylthiazole (3) with 4-hydroxythiophenol, displacement of the remaining alcohol through a three-step telescoped sequence involving an efficient cleavage of an aryl mesylate, and an efficient and practical method of introducing an isobutyric acid fragment.

Aza-cope rearrangement-mannich cyclizations for the formation of complex tricyclic amines: stereocontrolled total synthesis of (+/-)-gelsemine.

A detailed examination of the use of aza-Cope rearrangement-Mannich cyclization sequences for assembling the azatricyclo[4.4.0.0(2,8)]decane core of gelsemine is described. Iminium ions and N-acyloxyiminium ions derived from endo-oriented 1-methoxy- or 1-hydroxybicyclo[2.2.2]oct-5-enylamines do not undergo the first step of this sequence, cationic aza-Cope rearrangement, to form cis-hydroisoquinolinium ions. However, the analogous base-promoted oxy-aza-Cope rearrangement does take place to form cis-hydroisoquinolones containing functionality that allows iminium ions or N-acyloxyiminium ions to be generated regioselectively in a subsequent step. Mannich cyclization of cis-hydroisoquinolones prepared in this way efficiently assembles the azatricyclo[4.4.0.0(2,8)]decane unit of gelsemine. Using a sequential base-promoted oxy-aza-Cope rearrangement/Mannich cyclization sequence, gram quantities of azatricyclo[4.4.0.0(2,8)]decanone 18, a central intermediate in our total of (+/-)-gelsemine, were prepared from 3-methylanisole in 12 steps and 16% overall yield.

Use of the intramolecular Heck reaction for forming congested quaternary carbon stereocenters. Stereocontrolled total synthesis of (+/-)-gelsemine.

Intramolecular Heck reactions of alpha,beta-unsaturated 2-haloanilides derived from azatricyclo[4.4.0.0(2,8)]decanone 5 efficiently install the congested spirooxindole functionality of gelsemine. Depending upon the Heck reaction conditions and the nature of the beta-substituent, either products having the natural or unnatural configuration of the spirooxindole group are formed predominantly. Efforts to elaborate the hydropyran ring of gelsemine from the endo-oriented nitrile substituent of pentacyclic Heck product 18 were unsuccessful. Important steps in the ultimately successful route to (+/-)-gelsemine (1) are as follows: (a) intramolecular Heck reaction of tricyclic beta-methoxy alpha,beta-unsaturated 2-iodoanilide 68 in the presence of silver phosphate to form pentacyclic product 69 having the unnatural configuration of the spirooxindole fragment, (b) formation of hexacyclic aziridine 80 from the reaction of cyanide with intermediate 79 containing an N-methoxycarbonyl-beta-bromoethylamine fragment, (c) introduction of C17 by ring-opening of the aziridinium ion derived from aziridine 80, and (d) base-promoted skeletal rearrangement of pentacyclic equatorial alcohol 82 to form the oxacyclic ring and invert the spirooxindole functional group to provide hexacyclic gelsemine precursor 83.

Regioselective palladium-catalyzed arylation of 3-carboalkoxy furan and thiophene.

[reaction: see text] The regioselective palladium(0)-catalyzed arylation of 3-furoate and 3-thiophenecarboxylate esters with aryl bromides is described. Conditions were developed that allow for the selective synthesis of either 2-aryl or 5-aryl products.