MK 8876 / Merck (MSD) - LARVOL DELTA

Distinct Characteristic Binding Modes of Benzofuran Core Inhibitors to Diverse Genotypes of Hepatitis C Virus NS5B Polymerase: A Molecular Simulation Study. (PubMed, Int J Mol Sci) - "The benzofuran core inhibitors HCV-796, BMS-929075, MK-8876, compound 2, and compound 9B exhibit good pan-genotypic activity against various genotypes of NS5B polymerase...The interactions between the para-fluorophenyl groups at the C2 positions of the inhibitors and the residues at the binding pockets, together with the interactions between the substituents at the C5 positions and the residues at the reverse β-fold (residues 441-456), play a key role in recognition and the induction of the binding. The relevant studies could provide valuable information for further research and development of novel anti-HCV benzofuran core pan-genotypic inhibitors."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Cocrystal Synthesis through Crystal Structure Prediction. (PubMed, Mol Pharm) - "We have used a CSP-based cocrystal prediction method to rank ten potential cocrystal coformers by the energy of the cocrystallization reaction with an antiviral drug candidate, MK-8876, and a triol process intermediate, 2-ethynylglyclerol. Computational finite-temperature corrections enabled determination of relative crystallization propensities of the triol-DABCO cocrystals with different stoichiometries and prediction of the triol-l-proline polymorphs in the free-energy landscape. The triol-l-proline cocrystal was obtained during subsequent targeted cocrystallization experiments and was found to exhibit an improved melting point and deliquescence behavior over the triol-free acid, which could be considered as an alternative solid form in the synthesis of islatravir."

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Design and evaluation of novel tetracyclic benzofurans as palm site allosteric inhibitors of HCV NS5B polymerase. (PubMed, Bioorg Med Chem Lett) - "Similar to clinical developmental compound MK-8876, N-linked (compounds 1 and 2) and C-linked (compounds 3 and 4) tetracyclic structures maintained broad spectrum anti-replicon potency profiles and demonstrated moderate to excellent oral bioavailability and pharmacokinetic parameters across the three preclinical animal species. To better understand the importance of tetracyclic structures related to pan genotypic potency profiles especially against clinically relevant GT1a variants, the teracycles with different ring size were prepared and in vitro evaluations suggested compounds with six number ring have better overall potency profiles."

Journal • Hepatitis C Virus

Safety, pharmacokinetics, and pharmacodynamics of MK-8876 in participants with hepatitis C infection (MK-8876-003) (clinicaltrials.gov) - P1, N=50; Sponsor: Merck Sharp & Dohme Corp.; Recruiting; Primary completion date: Apr 2014 -> Aug 2014.

Trial primary completion date • Hepatitis C Virus

Achillion: Oppenheimer Healthcare Conference (Achillion) - Anticipated launch of MK 5172 + MK 8742 + MK 8876 triple combo for hep C infection in 2016/2017

Anticipated launch • Hepatitis C Virus

Multi-step parallel synthesis enabled optimization of benzofuran derivatives as pan-genotypic non-nucleoside inhibitors of HCV NS5B. (PubMed, Bioorg Med Chem Lett) - "In addition, the bicyclic compounds 9B exhibited improved FASSIF solubility over the tetracyclic compound MK-8876. This strategic approach demonstrated that, even within limited reaction scope, multi-step parallel libraries could provide access to more complex chemical space. This expedient access facilitates diverse, purpose-driven optimization of SAR and physicochemical properties."

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