The reactions of substituted phenolate anions with m-nitrophenyl, p-nitrophenyl, and 3,4-dinitrophenyl formates follow nonlinear Bransted-type correlations that might be taken as evidence for a change in the rate-limiting step of a reaction that proceeds through a tetrahedral addition intermediate. However, the correlation actually represents two different Bronsted lines that are defined by meta-and para-substituted phenolate anions and by meta-and para-substituted o-chlorophenolate anions. A concerted mechanism for both acetyl-and formyl-transfer reactions is supported by the absence of a detectable change in the Bronsted slope at ApK = 0 for the attacking and leaving phenolate anions within each class of Bronsted correlations. Regular increases in the dependence of log k on the pAa of the nucleophile with increasing pAa of the leaving group correspond to a positive interaction coefficient pxy = d/3lg/d(pA"uc) = d/3nuc/5(pAlg). The observation of two different Bronsted lines for the reactions of substituted phenolate anions with phenyl acetates is attributed to a steric effect that decreases the rate of reaction of substituted o-chlorophenolate anions by 25-50%. The reactions of metaand para-substituted phenolate and o-chlorophenolate anions with substituted phenyl acetate esters follow values of /3nlic = 0.53-0.66 and -j5lg = 0.50-0.63. The reactions of meta-and para-substituted phenolate anions with formate esters are ~103 times faster and follow smaller values of j6nuc = 0.43-0.64 and -/3|g = 0.31-0.48. However, the reactions of meta-and para-substituted o-chlorophenolate anions with the same formate esters follow larger values of /3nuc = 0.63-0.90 and -/3,g = 0.46-0.90. The large values of /3nuc and -/Slg for the reactions of substituted o-chlorophenolate anions with formate esters may arise from destabilization by the o-chloro group of a stacking interaction that is present in the transition state for reactions of formate esters, but not acetate esters.

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The anti-hepatitis C virus nucleotide prodrug GS-6620 employs a double-prodrug approach, with L-alanine-isopropyl ester and phenol moieties attached to the 5=-phosphate that release the nucleoside monophosphate in hepatocytes and a 3=-isobutyryl ester added to improve permeability and oral bioavailability. Consistent with the stability found in intestinal homogenates, following oral administration, intact prodrug levels in blood plasma were the highest in dogs, followed by monkeys, and then were the lowest in hamsters. In contrast, liver levels of the triphosphate metabolite at the equivalent surface area-adjusted doses were highest in hamsters, followed by in dogs and monkeys. Studies in isolated primary hepatocytes suggest that relatively poor oral absorption in hamsters and monkeys was compensated for by relatively efficient hepatocyte activation. As intestinal absorption was found to be critical to the effectiveness of GS-6620 in nonclinical species, stomach pH, formulation, and food effect studies were completed in dogs. Consistent with in vitro absorption studies in Caco-2 cells, the absorption of GS-6620 was found to be complex and highly dependent on concentration. Higher rates of metabolism were observed at lower concentrations that were unable to saturate intestinal efflux transporters. In first-in-human clinical trials, the oral administration of GS-6620 resulted in poor plasma exposure relative to that observed in dogs and in large pharmacokinetic and pharmacodynamic variabilities. While a double-prodrug approach, including a 3=-isobutyryl ester, provided higher intrinsic intestinal permeability, this substitution appeared to be a metabolic liability, resulting in extensive intestinal metabolism and relatively poor oral absorption in humans.A pproximately 170 million people worldwide are infected by the hepatitis C virus (HCV), and nearly 2% of the U.S. population is estimated to have HCV (1). HCV is a major health issue since approximately 15 to 35% of those who are chronically infected will develop cirrhosis and 1 to 3% will progress to hepatocellular carcinoma over 30 years (2). Currently, the recently approved protease inhibitors (boceprevir and telaprevir) are used in combination with pegylated interferon alpha plus ribavirin (PEG-RBV) for the treatment of chronic HCV infection. While these treatments show improved response rates and the potential for shorter duration of treatment over PEG-RBV alone, they lack efficacy against genotypes other than genotype 1, require thricedaily dosing, and cause additional side effects from the new directacting antivirals on top of the already-challenging tolerability profile of PEG-RBV. Therefore, there is a need for more potent anti-HCV compounds with improved clinical efficacy and greater tolerability in order to more broadly address the unmet medical needs of those with chronic HCV infection. Combinations of antiviral agents targeting viral proteins essential to HCV replication have the potential to achieve increased clinical efficacy across HCV genotypes, ...

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Equilibrium constants and the rates of ketone-enolate ion equilibration have been measured for the deprotonation of eight 3-(X-phenylacetyl)pyridines 1 (pKa 13.2 for X = H), ten 4-(X-phenylacetyl)pyridines 2 (pKa 12.2 for X = H), nine 1 -methyl-3-(X-phenylacetyl)pyridinium cations 3 (pK, 10.32 for X = H), and ten l-methyl-4-(X-phenylacetyl)pyridinium cations 4 (pKa 9.02 for X = H) in aqueous solution at 25 'C and ionic strength 0.1. The pKa values for each of these series of ketones are closely correlated with the pKa values for the corresponding ring-substituted phenols. Pseudo-first-order rate constants for deprotonation of both series of neutral ketones (1, 2 ) are strictly proportional to hydroxide ion concentration in the range pH 11-13, and second-order rate constants ( k o~) for hydroxide ion catalyzed deprotonation have been evaluated. The pseudo-first-order rate constants ( k d ) for deprotonation of both series of N-methyl cations (3,4) are subject to hydroxide ion catalysis (second-order rate constant koH) but display kinetic saturation effects consistent with kinetically controlled hydroxide ion addition to the carbonyl group of the ketone. In basic solution this addition competes with the thermodynamically more favorable enolate ion formation. These four series of ketones (1-4) display quite different linear Bransted plots (log koH vs pKa), with relative reactivities at constant pKa being in the order 4 < 3 < 2 < 1. The 4-NO2 and 4-CN substituents in all four series of ketones, and also 4 with X = W H 3 , show negative deviations from these Bransted relationships. These deviations, and also the relative reactivities for 1-4, can be traced to imbalances in both a-electron delocalization and solvent reorganization in the transition states relative to the enolate ion products. Bransted a values cover the range 0.66-0.76 and vary in the order

cm-I; MS m / e (re1 intensity) 292 (M+, 41). 261 (70), 260 (56), 75 (100).The above crude 21 was treated with methanolic NaOH as described for 20 to give 44 mg (94%) of 23: 'H NMR (CDCI,) 6 5.43 (dd, J = 1.5,2.5Hz,1H),5.32(brs,1H),4.23(d,J=9.3Hz,1H),4.11(d, J = 9.3 Hz, 1 H), 3.68 (s, 3 H), 3.40 (s, 3 H), 2.86 (ddd,

The rates of hydrolysis of valganciclovir to ganciclovir and L-valine and isomerization of the R and S diastereomers of valganciclovir in aqueous buffer solution from pH 3.8 to 11.5 were determined at 37 degrees C. The kinetics of hydrolysis were first order for at least two half-lives in neutral and basic solutions. In acidic solutions where less than 10% degradation occurred, the rate of hydrolysis was determined assuming a first-order loss in drug. At 37 degrees C and pH 7.08, the half life is 11 h. The maximum stability at the pH values studied occurred at pH 3.81 with a half life of 220 days. The kinetics of the approach to equilibrium for the isomerization were first order and the ratio of the R:S isomer at equilibrium was 52:48. Isomerization was approximately 10 fold faster than hydrolysis over the pH range studied with a half-life at pH 7.01 of 1 h. The maximum stability toward isomerization (t1/2>533 h) occurs at a pH below 3.8. The pH-rate profile for the hydrolysis and the isomerization reaction are best described by hydroxide ion catalyzed mechanisms. In acidic and neutral solutions, the hydroxide reacts with the protonated form of the drug, while in basic solutions, the hydroxide reacts with the neutral form of the drug.

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