Development of a New Structural Class of Broadly Acting HCV Non‐Nucleoside Inhibitors Leading to the Discovery of MK‐8876

Abstract

Studies directed at developing a broadly acting non-nucleoside inhibitor of HCV NS5B led to the discovery of a novel structural class of 5-aryl benzofurans that simultaneously interact with both the palm I and palm II binding regions. An initial candidate was potent in vitro against HCV GT1a and GT1b replicons, and induced multi-log reductions in HCV viral load when orally dosed to chronic GT1 infected chimpanzees. However, in vitro potency losses against clinically relevant GT1a variants prompted a further effort to develop compounds with sustained potency across a broader array of HCV genotypes and mutants. Ultimately, a biology and medicinal chemistry collaboration led to the discovery of the development candidate MK-8876. MK-8876 demonstrated a pan-genotypic potency profile and maintained potency against clinically relevant mutants. It demonstrated moderate bioavailability in rats and dogs, but showed low plasma clearance characteristics consistent with once-daily dosing. Herein we describe the efforts which led to the discovery of MK-8876, which advanced into Phase 1 monotherapy studies for evaluation and characterization as a component of an all-oral direct-acting drug regimen for the treatment of chronic HCV infection.

A review on HCV inhibitors: Significance of non-structural polyproteins

“…The potency of HCV-796 compound was further increased to 5 fold by modifying the aliphatic alcohol with boronic acid (GSK5852) (169, 1a & 1b, EC 50¼ 3 & 6 nM) and resulting structure was successful to inhibit the mutated HCV isoforms [85]. [86]. Additionally, the replacement of oxazinoindole of MK-8876 with linear aryl rings provided BMS-929075 as pan HCV NS5B inhibitor (171, 1a & 1b, EC 50¼ 9 & 4 nM) as clinical candidate with improvised oral bioavailability and pharmacokinetics [87].…”

[RhCp*Cl2]2-Catalyzed Indole Functionalization: Synthesis of Bioinspired Indole-Fused Polycycles

“…Intriguingly, pyrrolo­[1,2- c ]­pyrimidin-1­(2 H )-ones, pyrimido­[1,6- a ]­indol-1­(2 H )-ones, 1 H -[1,3]­oxazino­[3,4- a ]­indol-1-one, etc., scaffolds are the among integral parts of fluorescent materials and with diverse biological activity. , As a result, both natural products and medicinal chemistry paid close attention to synthesizing these compounds . In order to quickly fabricate 2 H -pyrimido­[1,6- a ]­indol-1-one derivatives, Chen and co-workers previously developed the Rh­(III)-catalyzed [4 + 2] annulation of N -alkylaminocarbonyl indole with acyl diazo compounds .…”

“…https://doi.org/10.1021/acsomega.3c02510ACS Omega XXXX, XXX, XXX−XXX 1(2H)-ones, 1H-[1,3]oxazino[3,4-a]indol-1-one, etc., scaffolds are the among integral parts of fluorescent materials and with diverse biological activity 132,133. As a result, both natural products and medicinal chemistry paid close attention to synthesizing these compounds 134. In order to quickly fabricate 2H-pyrimido[1,6-a]indol-1-one derivatives, Chen and co-work-carboxamide indoles 110 with iodonium ylides 111 to produce synthetically significant N-heterocycles 112 and 113, using iodonium ylide as a precursor to a carbene (Scheme 27) 137.…”

Rh(III)-Catalyzed Chemodivergent Annulations between Indoles and Iodonium Carbenes: A Rapid Access to Tricyclic and Tetracyclic N-Heterocylces

“…In nitrogen heterocycles, indole and pyrrole scaffolds are central structural motifs and can be found in a large number of natural products, pharmaceuticals, and manufactured functional molecules . In particular, pyrimido­[1,6- a ]­indol-1­(2 H )-ones, pyrrolo­[1,2- c ]­pyrimidin-1­(2 H )-ones, and 1 H -[1,3]­oxazino­[3,4- a ]­indol-1-one scaffolds are an integral part of fluorescent materials and diverse biologically active compounds such as 5-HT3 receptor antagonists, antihypertensive agents, CNS depressants, and others. , Consequently, the synthesis of these derivatives gained considerable attention in both organic and medicinal chemistry . Although numerous methods have been well-developed to assemble these moieties, most of the methods involve multiple synthetic steps and harsh reaction conditions.…”

“…The reaction affords a wide range of 2 H -pyrimido­[1,6- a ]­indol-1-ones and 1 H -[1,3]­oxazino­[3,4 -a ]­indol-1-ones with moderate to excellent yields under mild reaction conditions (Scheme d). The desired analogues are core structures of many biologically active compounds. , …”