ABSTRACT:We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure−activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.

GPR120 (FFAR4) is a fatty acid sensing G protein coupled receptor (GPCR) that has been identified as a target for possible treatment of type 2 diabetes. A selective activator of GPR120 containing a chromane scaffold has been designed, synthesized, and evaluated in vivo. Results of these efforts suggest that chromane propionic acid 18 is a suitable tool molecule for further animal studies. Compound 18 is selective over the closely related target GPR40 (FFAR1), has a clean off-target profile, demonstrates suitable pharmacokinetic properties, and has been evaluated in wild-type/ knockout GPR120 mouse oGTT studies.

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ABSTRACT:We have previously reported the discovery of our P2−P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pangenotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants. KEYWORDS: Antiviral, HCV, NS3/4a, macrocycle, pan-genotypic, genotype 3a A n estimated 180 million people worldwide are chronically infected with the hepatitis C virus (HCV) and about 20% of this population is at a risk of developing liver cirrhosis, which can lead to end stage liver disease and hepatocellular carcinoma.1−3 The majority of infections in the developed world are caused by HCV genotypes 1, 2, and 3. While standard of care treatment with pegylated IFN-α (P) and ribavirin (R) results in a cure rate of ∼70−90% in patients infected with genotypes 2 and 3, the cure rate is only ∼45% for genotype 1 infected patients. 4 The addition of direct acting HCV serine protease NS3/4a inhibitors such as boceprevir or telaprevir to PR treatment regimens has significantly improved the sustained virological response (SVR) rate to up to 75% for naıve HCV genotype 1 patients (representing more than 70% of all cases of chronic HCV infection in the United States). 5,6 Furthermore, side effects associated with PR and first generation NS3/4a inhibitors, the rapid emergence of drug resistance, and suboptimal SVR have led to the development of more potent NS3/4a protease inhibitors with a higher barrier to resistance. These drug candidates in combination with compounds from additional classes of HCV direct acting antivirals offer promising all-oral interferon sparing treatment regimens. 7 We have previously reported the discovery of our P2−P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172 ( Figure 1), which is currently undergoing clinical trials. 8,9 Preclinically, MK-5172 demonstrated broad genotype and mutant enzyme potency and cellular activity. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79 (Figure 2). Although in the NS3 protease structure of the catalytic d...

The ever-growing prevalence of type 2 diabetes in the world has necessitated an urgent need for multiple orally effective agents that can regulate glucose homeostasis with a concurrent reduction in body weight. G-Protein coupled receptor 119 (GPR119) is a GPCR target at which agonists have demonstrated glucose-dependent insulin secretion and shows beneficial effects on glycemic control. Herein, we describe our efforts leading to the identification of a potent, oral GPR-119 agonist, MK-8282, which shows improved glucose tolerance in multiple animal models and has excellent off-target profile. The key design elements in the compounds involved a combination of a fluoro-pyrimidine and a conformationally constrained bridged piperidine to impart good potency and efficacy.

A general strategy for the preparation of the family of exo-[n.m.n.m]metacyclophanes (n,m > or = 3) in 6-steps (starting from 2-bromoanisole) that utilizes a [2 + 2] approach to furnish the exo-metacyclophane ring in good to moderate yield is described. The soluble copper catalyst [CuBr-LiSPh-LiBr-THF] is used to efficiently couple Grignard and alkyl or ether tosylate reagents in several of the synthetic steps, including the ring construction in the final step. The exo-[n.m.n.m]metacyclophane ring is conformationally mobile on the NMR time scale, and X-ray crystallography reveals that exo-[3.3.3.3]metacyclophane 2a assumes a cone conformation, and that exo-[6.6.6.6]metacyclophane 6a assumes a chair conformation. Molecular mechanics calculations show that both conformations for each exo-metacyclophane are very similar in energy. Regiocontrol over the alkylation and acylation of the phenolic oxygens of 2b is problematic, although the preparation of the tetraacetylated 18 and alkylation of 2b with CH2BrCl to furnish the methylene-linked mono- and bis-adducts 19 and 20 are straightforward.

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