Current Topics in Medicinal Chemistry - Volume 7, Issue 13, 2007

Epidemiological figures indicate that today 40 million people are living with HIV/AIDS including 2.3 million children. 170 million people worldwide are infected with hepatitis C (HCV) virus, with this being the second most common etiological agent of chronic liver disease and hepatocellular carcinoma. The four reviews in this issue discuss the most recent approaches towards the care of these two types of viral diseases. The first two contributions are dedicated to the most recent strategies in the fight against AIDS. June 2006 marked the 25th anniversary of the discovery of HIV/AIDS and since that fateful report on the 5th June 1981, this disease has claimed the lives of over 25 million people worldwide and it has afflicted every corner of the world crossing geographic, cultural, ethnic and socioeconomic boundaries. Currently, the therapy for AIDS relies on drugs with three mechanisms: HIV protease, HIV reverse transcriptase nucleoside and non nucleoside inhibitors. Unfortunately the ability of the virus to mutate and become resistant to these treatments has led to an increasing proportion of the infected population harboring virus that is resistant to these classes of drugs. In this issue the most promising scientific findings about the discovery of two new classes of drugs will be presented: Melissa S. Egbertson summarizes some of the developments in Merck Laboratories on HIV Integrase Inhibitors and Claudiu Supuran and coauthors illustrate the most recent progress in the development of HIV entry inhibitors. Melissa Egbertson describes efforts in the exploration of Integrase activity and the design of potent and efficacious inhibitors of HIV Integrase. An important step in the evolution of the HIV Integrase program at Merck was the development of a biochemical assay separating the final strand transfer step from the earlier assembly and processing step; using this assay, compounds were screened for their ability to act solely as inhibitors of strand transfer. The evolution from the diketoacid scaffold to the 1,6-naphthyridine template is reported and the optimization route, towards compounds selected for further preclinical evaluation, is described. Claudiu T. Supuran and coauthors review the recent developments in the field of HIV entry inhibitors. Viral entry into the cell takes place in three steps: attachment of the virus to the host cell through the formation of a complex between the trimeric gp120-gp41 viral glycoproteins, the CD4 receptor and the chemokine coreceptor (CCR5 or CXCR4); interaction of the virus with the co-receptors and fusion of the virus and host cell membranes. All three steps have been considered for the design of HIV entry inhibitors and these different types of agents have been reviewed by the authors. They also underline the potential interference of these compounds with homeostasis of the immune system and the possible risk of inducing or shutting off inflammatory pathways. A careful design to achieve selectivity over the host receptors is considered of fundamental importance for the success of these agents. The third and the fourth contributions are dedicated to the efforts towards a therapy for Hepatitis C. Hepatitis C is currently treated with PEGylated α-interferon alone or in combination with ribavirin and no vaccine is available. Up to 80% of genotype- 2 infected patients respond to interferon therapy whereas only about 50% of genotype-1 infected people show a sustained response. In recent years drug development efforts have mainly been directed at targeting inhibition of two viral enzymes: NS3 protease and NS5B RNA dependent RNA polymerase.

Replication of the human immunodeficiency virus (HIV) is dependent upon the enzyme HIV integrase (IN), one of three essential enzymes encoded in the viral genome. HIV-1 IN catalyzes the insertion of the proviral DNA into the host genome (strand transfer). HIV-1 IN therefore presents an attractive chemotherapeutic target for the treatment of HIV infection and AIDS that could provide patients and physicians with an additional option for treatment. Assays were developed to identify inhibitors of IN strand transfer. Diketoacid lead compounds were explored and developed into a variety of heterocyclic templates that are potent inhibitors of integrase strand transfer with suitable medicinal chemical properties for treating HIV infection and AIDS. The 1,6-naphthyridine L-870810 (Antiviral activity in cells IC95 NHS = 102 nM, n=237), was shown to be efficacious in reducing viral RNA by 1.7 log units after doses of 400mg BID to HIV infected patients. Optimization of physical properties led to L-900564, an inhibitor of HIV IN that has excellent cell potency in the presence of protein (Antiviral activity in cells IC95 NHS = 16 nM, n=15), excellent activity against mutants raised to HIV integrase inhibitors, and a very good pharmacokinetic profile..

HIV entry and fusion are two steps in the viral life cycle that can be targeted by several classses of antiviral drugs. The discovery of chemokines focused the attention on cellular coreceptors used by the virus for entering within cells, and to the various steps of such processes which are subject to interactions with small molecules. Intense research led to a wide range of effective compounds that are able to inhibit these initial steps of viral replication. All steps in the process of HIV entry into the cell may be targeted by specific compounds that may be developed as novel types of antiretrovirals. Thus, several inhibitors of the gp120 - CD4 interaction have been detected so far (zintevir, FP-21399 and BMS-378806 in clinical trials). Small molecule chemokine receptor antagonists acting as HIV entry inhibitors also were described in the last period, which interact both with the CXCR4 coreceptor (such as AMD3100; AMD3465; ALX40-4C; T22, T134 and T140), or which are antagonist of the CCR5 coreceptor (TAK-779, TAK-220, SCH-C, SCH-D, E913, AK- 602 and NSC 651016 in clinical trials), together with new types of fusion inhibitors possessing the same mechanism of action as enfuvirtide (such as T1249). Recently, a third family of antivirals started to be used clinically (in addition to the reverse transcriptase and protease inhibitors), with the advent of enfuvirtide (T20), the first fusion inhibitor to be approved as an anti-HIV agent. Some of these compounds demonstrated in vitro synergism with other classes of antivirals, offering thus the rationale for their combination in therapies for HIV-infected individuals. Many HIV entry and fusion inhibitors are currently investigated in controlled clinical trials, and there are a number of them that is bioavailable as oral formulations. This is an essential feature for an extended use of these compounds with the purpose of ameliorating adherence of patients to these medications and preventing the development of drug resistance.

HCV NS3, a serine protease, that when bound to NS-4A cofactor facilitates development of mature virons by catalyzing cleavage of a single polyprotein to form functional and structural proteins of HCV. X-ray structure of the enzyme reveal a very shallow binding pocket at the catalytic site which makes development of inhibitors a daunting task. Various novel approaches have been used to design, preorganized, depeptidized macrocyclic inhibitors linking the P2-P4 residues and P1-P3 groups. The design and structure activity relationship of these macrocyclic inhibitors are reviewed in the following article. X-ray structure of inhibitor bound to the active site of the enzyme is also discussed. Macrocyclization proved to be an effective tool for depeptidization of peptidic inhibitors, imparting enhanced metabolic stability and improved pharmacokinetic properties in the resultant molecules.

The global prevalence of hepatitis C virus (HCV) infection and the serious consequences associated with the chronic state of the disease have become a worldwide health problem. A combination therapy comprising Interferon-alpha and Ribavirin represents the current standard treatment for chronic HCV infection, although it has demonstrated limited success and causes serious side effects. Promising alternative approaches toward the control of HCV infection include the development of small molecule inhibitors of viral enzymes interfering with the essential steps in the life cycle of the virus. In this review we will focus on inhibitors of the HCV-encoded NS5B RNA-dependent RNA polymerase (NS5B RdRp) which is essential for viral replication and has been recognized as a prime target for therapeutic intervention.

Chantix™ - the first non-nicotine-containing medication for smoking cessation. Nicotine is a highly addictive, bioactive small molecule found in tobacco (e.g., cigarettes) which produces physical dependence [1]. Despite serious tobacco-related illnesses (cancer, respiratory disease and cardiovascular disease), most smokers fail to quit due to the addictive nature of nicotine [2]. Few pharmacotherapies are available for nicotine addiction, and those that are, nicotine replacement therapy and the antidepressant bupropion, have but modest long-term success [3]. An alternative, non-nicotine-containing approach centers on neuronal nicotinic acetylcholine receptors (nAChRs), and in particular, the α4β2 nAChR is a target of interest for the development of smoking cessation therapies due to its location on presynaptic terminals in the striatum and its role in modulating dopamine release [4]. In the mid 90s, Pontieri and Corrigall reported that the reinforcing effects of nicotine are mediated by high affinity α4β2 nAChRs in the mesolimbic dopamine system [5,6]. Activation of α4β2 nAChRs triggers mesolimbic dopamine release which elicits reward signal to higher cortical centers. Repeated abuse of nicotine triggers rapid and variable increases in dopamine release, facilitating both association and learning that leads to dependence [7]. Deletion of either the α4 or β2 subunit of α4β2 nAChRs led to an attenuation of the effects of nicotine and further supported the key role of mesolimbic α4β2 nAChRs in nicotine addiction [3]. These data led to the hypothesis that a partial agonist of α4β2 nAChRs would relieve the cravings and withdrawal symptoms in smokers trying to quit as well as reducing or eliminating the reinforcing element of tobacco [3, 8]. Achieving subtype selectivity within the nAChRs, which consist of many α and β subunit combinations, is a huge challenge, and developing a selective α4β2 nAChR partial agonist through a classical HTS approach seems daunting. However, Pfizer delivered a potent partial agonist of α4β2 nAChR Chantix™, also known as varenicline tartrate, which was approved by the FDA in 2006 for the cessation of smoking [3, 9]. The origin of Chantix™ can be traced back to a small, conformationally rigid plant alkaloid known as cytosine [10-13]. Equilibrium binding assays demonstrated that cytisine was selective for the α4β2 subtype. In functional assays, cytisine showed greater potency at α4β2 receptors than any other subtype; however, it does display a wide range of efficacy at multiple subunit congeners. In fact, cytisine, while a partial agonist at α4β2, it is also a high efficacy agonist at α7 and at various β4 variant. Studies demonstrated that structural manipulations of cytisine resulted in changes in efficacy at multiple neuronal nAChRs. The structure of Chantix™ is loosely based on cytisine, and it was the partial agonist activity of cytisine that led to the development of Chantix™. Chantix™ is a orally bioavailable, partial agonist of α4β2 nAChR (EC50 = 2.3 μM, 13.4% of ACh max), but also activates other subtypes with a range of potencies and efficacies. Five separate clinical trials demonstrated the superior efficacy, tolerability and safety of Chantix™ relative to the other available pharmacotherapies. Indeed, after 12 weeks, 44% of patients taking a 1 mg dose of Chantix™ quit smoking as compared to 17% on placebo. After 52 weeks, prevalence abstinence rates were 36.7% for Chantix™ as compared to 7.9% for placebo [3, 8-13]. The development of Chantix™, exclusively for the treatment of nicotine addiction, represents a huge advance for an unmet medical need, and once again highlights how a natural product inspired and facilitated the discovery of a major new pharmaceutical agent.