Novel potent and selective diarylimidazole inhibitors of p38 MAP (mitogen-activated protein) kinase are described which have activity in both cell-based assays of tumor necrosis factor-alpha (TNF-alpha) release and an animal model of rheumatoid arthritis. The SAR leading to the development of selectivity against c-Raf and JNK2alpha1 kinases is presented, with key features being substitution of the 4-aryl ring with m-trifluoromethyl and substitution of the 5-heteroaryl ring with a 2-amino substituent. Cell-based activity was significantly enhanced by incorporation of a 4-piperidinyl moiety at the 2-position of the imidazole which also enhanced aqueous solubility. In general, oral bioavailability of this class of compounds was found to be poor unless the imidazole was methylated on nitrogen. This work led to identification of 48, a potent (p38 MAP kinase inhibition IC50 0.24 nM) and selective p38 MAP kinase inhibitor which inhibits lipopolysaccharide-stimulated release of TNF-alpha from human blood with an IC50 2.2 nM, shows good oral bioavailability in rat and rhesus monkey, and demonstrates significant improvement in measures of disease progression in a rat adjuvant-induced arthritis model.

A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1−3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.KEYWORDS: hepatitis C, HCV, MK-5172, macrocycle, genotype 3a, mutant enzymes H epatitis C virus (HCV) is a chronic liver infection that affects an estimated 130−170 million people worldwide. 1,2 HCV displays a high degree of genetic heterogeneity and can be classified into six major genotypes with different geographic distributions: genotypes 1, 2, and 3 account for more than 90% of the infections in the developed world. Treatment for HCV is based on combination therapy with pegylated interferon-α and ribavirin. 3 Sustained viral response is seen in ∼45% of HCV genotype 1-infected patients treated for 48 weeks and in ∼80% of genotype 2-and 3-infected patients treated for 24 weeks. Interferon and ribavirin therapy is also associated with a number of serious side effects, limiting the number of patients who may be treated. 4 There is a compelling medical need for new oral therapeutic agents with improved efficacy and tolerability. Several promising antiviral targets for HCV have emerged, 5 with NS3/4a protease inhibitors showing perhaps the most dramatic antiviral effects. 6 Clinical proof of concept for this mechanism was first achieved with BILN-2061. 7 Other compounds have entered clinical trials, including telaprevir 8 and boceprevir, 9 both of which are now marketed treatments for use in combination with a standard of care. Compounds currently in development include TMC-435 10 and We have disclosed a molecular modeling-derived strategy that led us to design HCV NS3/4a protease inhibitors that contain the P2 to P4 macrocyclic constraint. 12 This design arose from an analysis of the crystal structure of full-length NS3/4A with and without inhibitors docked in the active site. 13 Our strategy coupled with a modular synthetic approach, which relies on a key ring-closing metathesis (RCM) reaction, 14 allowed for the rapid exploration of these molecules and the identification of clinical candidates, vaniprevir (1) 15,16 and MK-1220 (2). 17 Herein, we describe the discovery of a clinical candidate with broad activity across genotypes (gt) and resistant HCV variants. 18,19 With the development of vaniprevir progressing, we set a goal for the ongoing discovery program to be the identification of a second generation NS3/4a protease inhibitor. We wanted to maintain or improve the PK profile seen with our previous compounds and make significant improvements in activity against the gt 3a enz...

A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.

Molecular modeling of inhibitor bound full length HCV NS3/4A protease structures proved to be a valuable tool in the design of a new series of potent NS3 protease inhibitors. Optimization of initial compounds provided 25a. The in vitro activity and selectivity as well as the rat pharmacokinetic profile of 25a compare favorably with the data for other NS3/4A protease inhibitors currently in clinical development for the treatment of HCV.