Synthesis and evaluation of non-dimeric HCV NS5A inhibitors.

Based on the symmetrical bidentate structure of the NS5A inhibitor BMS-790052, a series of new monodentate molecules were designed. The synthesis of 36 new non-dimeric NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. Among them compound 5a showed picomolar range activity along with an excellent selectivity index (SI > 90,000).

Scaleable processes for the synthesis of (-)-ß-D-2,6-diaminopurine dioxolane (Amdoxovir, DAPD) and (-)-ß-D-2-aminopurine dioxolane (APD).

An efficient and scalable synthesis of (-)-DAPD and (-)-APD has been developed. We discovered that t-butyl cyanoacetate can be used as a new additive for the sugar nucleoside base coupling step en route to DAPD with improved ß-selectivity and an isolated yield four fold greater than the original process scale method. Using this new process, (-)-DAPD has been prepared on greater than 20 g scale. In the synthesis of (-)-APD, a key enzyme-catalyzed hydrolysis reaction afforded the water-soluble deprotected α-anomer while leaving the ß-anomer completely untouched.

Synthesis and evaluation of novel potent HCV NS5A inhibitors.

Judicious modifications to the structure of the previously reported HCV NS5A inhibitor 1, resulted in more potent anti-HCV compounds with similar and in some cases improved toxicity profiles. The synthesis of 19 new NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. For the most potent compounds chemical stability, stability in liver microsomes and inhibition of relevant CYP450 enzymes is also presented.

Synthesis and biological evaluation of new potent and selective HCV NS5A inhibitors.

NS5A inhibitors are a new class of direct-acting antiviral agents which display very potent anti-HCV activity in vitro and in humans. Rationally designed modifications to the central biphenyl linkage of a known NS5A series led to selection of several compounds that were synthesized and evaluated in a HCV genotype 1b replicon. The straight triphenyl linked compound 11a showed similar anti-HCV activity to the clinical compound BMS-790052 and a superior cytotoxicity profile in three different cell lines, with an EC(50) value of 26 pM and a therapeutic index of over four million in an HCV replicon assay. This triphenyl analog warrants further preclinical evaluation as an anti-HCV agent.

Advances in nucleoside monophosphate prodrugs as anti-HCV agents.

Nucleoside monophosphate prodrugs that are eventually bioconverted to the active nucleoside triphosphate (NTP) offer the potential to deliver increased intracellular NTP levels and/or organ-specific NTP enhancement. There are several classes of monophosphate prodrugs that have been applied to HCV drug discovery, and some of these approaches are currently being evaluated in humans. This review discusses recent advances in monophosphate prodrug approaches to improve oral absorption, stability and pharmacokinetic profile, including their advantages and potential pitfalls.

Application of cross-conjugated heteroaromatic betaines to the synthesis of the schizozygane alkaloid (+/-)-strempeliopine.

An efficient stereocontrolled route to the isoschizozygane alkaloid core has been developed utilizing an intramolecular 1,4-dipolar cycloaddition of a cross-conjugated heteroaromatic betaine. The resulting cycloadduct undergoes loss of COS, and further reduction delivers a 5a-azaacenaphthylene intermediate that was transformed into the isoschizozygane skeleton upon treatment with acid. A variation of this tactic was then employed for a synthesis of the hexacyclic framework of the shizozygane alkaloid (+/-)-strempeliopine. The key step of the synthesis corresponds to an intramolecular 1,4-dipolar cycloaddition of a heteroaromatic betaine across a tethered 4-((2-nitrophenyl)but-3-enyl) side chain. Catalytic reduction of the nitro group followed by reaction with NBS resulted in the formation of the required pentacyclic indoline framework of the target alkaloid. Closure of the final ring of the shizozygane skeleton was carried using an oxidative cyclization.

Internal azomethine ylide cycloaddition methodology for access to the substitution pattern of aziridinomitosene A.

Highly substituted, tethered alkyne dipolarophiles participate in the internal 2 + 3 cycloaddition with azomethine ylides generated by treatment of oxazolium salts with cyanide ion. Starting from oxazole 26, a sequence of N-methylation, cyanide addition, and electrocyclic ring opening of a 4-oxazoline intermediate affords the indoloquinone 31 in a one-pot process. A similar reaction from the protected alkynol derivative 25 affords the sensitive, but isolable, enone 32, and subsequent oxidation affords 31 and the deprotected quinone alcohol 34. Related azomethine cycloaddition methodology via intramolecular oxazolium salt formation from 43 or 46 is also demonstrated and allows the synthesis of quinone 45 and derived structures having the substitution pattern of aziridinomitosene A. Removal of the N-trityl protecting group could not be achieved without aziridine cleavage.