The structures of both the native holo-HCV NS3/4A protease domain and the protease domain with a serine 139 to alanine (S139A) mutation were solved to high resolution. Subsequently, structures were ...determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contribution to the binding energy arises from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets the numbering of the subsites is as defined in Berger, A.; Schechter, I. Philos. Trans. R. Soc. London, Ser. B 1970, 257, 249−264. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease that is currently in clinical trials.
Increasing the efficiency of the drug discovery process is a challenge faced by drug hunters everywhere. One strategy medicinal chemists employ to meet this challenge is learning from knowledge ...sources within and beyond their organization. In this Perspective, we discuss the evolution of mechanisms for medicinal chemistry knowledge capture and sharing at Merck & Co. over the past 15 years. We describe our approach to knowledge management and report on the multiple enduring and complementary teams and initiatives we have created to capture and share knowledge within a geographically diverse medicinal chemistry community. In addition, this Perspective will share the benefits we have observed and also reflect on what has allowed our efforts to be both successful and sustainable.
Efficient and high yielding stereoselective assembly of the tetrasaccharyl cap region of the lipophosphoglycan from the protozoan parasite Leishmania using the n-pentenyl glycoside protocol is ...described in this paper. Both convergent and linear syntheses lead to the protected tetrasaccharide 14; however, the convergent assembly is more efficient in terms of product recovery. Regioselective reductive cleavage of benzylidene acetal 4 with triethylsilane−trifluoroacetic acid system liberates the required C-4 OH in excellent yield, without affecting the resident chloroacetate functionality.
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Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the ...only therapeutic regimens are subcutaneous interferon-α or polyethylene glycol (PEG)-interferon-α alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.
HCV infection affects more than 170 million people worldwide and many of those patients will reach the end stage complications of the disease which include hepatocarcinoma and liver failure. The ...success rate for treatment of patients infected with genotype-1 is about 40%. Therefore, novel treatments are needed to combat the infection. The HCV NS3 protease inhibitor Boceprevir (1) was reported by our research group and efforts continue for the discovery of more potent compounds with improved pharmacokinetic profiles. A new series of HCV NS3 protease inhibitors having a cyclic sulfone P3-cap have been discovered. Compounds 43 and 44 showed K i* values in the single-digit nM range and their cellular potency was improved by 10-fold compared to 1. The pharmacokinetic profiles of 43 and 44 in rats and monkeys were also improved to achieve higher plasma levels after oral administration.
The development of a double addition reaction of alkoxylmethyl nucleophiles to a variety of functionalized aryl and alkyl esters to give polyoxygenated products is reported. Key features include ...broad electrophile substrate scope and good yields. Structurally diverse nucleophiles were investigated and were found to successfully undergo diaddition. This development now allows facile access to this novel class of polyoxygenated molecules.
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Novel substituted thiazole4,5-
cpyridines have been synthesized in good yields from unsubstituted thiazole4,5-
cpyridine.
Novel substituted thiazole4,5-
cpyridines have been synthesized in good ...yields from unsubstituted thiazole4,5-
cpyridine using direct C–H coupling reactions and N-oxide rearrangement chemistry.
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The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy ...underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC90 by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K i* = 4 nM, EC90 = 40 nM). Systematic optimization of different positions (P′, P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K i* = 4 nM, EC90 = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.
Novel 2′-modified guanosine nucleosides were synthesized from inexpensive starting materials in 7-10 steps via hydroazidation or hydrocyanation reactions of the corresponding 2′-olefin. The antiviral ...effectiveness of the guanosine nucleosides was evaluated by converting them to the corresponding 5′-O-triphosphates (compounds 38-44) and testing their biochemical inhibitory activity against the wild-type NS5B polymerase.
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In the search for a second generation HCV protease inhibitor, molecular modeling studies of the X-ray crystal structure of Boceprevir®
1 bound to the NS3 protein suggest that expansion into the S4 ...pocket could provide additional hydrophobic Van der Waals interactions. Effective replacement of the P4
tert-butyl with a cyclohexylmethyl ligand led to inhibitor
2 with improved enzyme and replicon activities. Subsequent modeling and SAR studies led to the pyridine
38 and sulfone analogues
52 and
53 with vastly improved PK parameters in monkeys, forming a new foundation for further exploration.
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