We have analyzed the rings, ring systems, and frameworks in drugs listed in the FDA Orange Book to understand the frequency, timelines, molecular property space, and the application of these rings in different therapeutic areas and target classes. This analysis shows that there are only 351 ring systems and 1197 frameworks in drugs that came onto the market before 2013. Furthermore, on average six new ring systems enter drug space each year and approximately 28% of new drugs contain a new ring system. Moreover, it is very unusual for a drug to contain more than one new ring system and the majority of the most frequently used ring systems (83%) were first used in drugs developed prior to 1983. These observations give insight into the chemical novelty of drugs and potentially efficient ways to assess compound libraries and develop compounds from hit identification to lead optimization and beyond.

The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.

The urgent need for efficacious drugs to treat chronic hepatitis C virus (HCV) infection requires a concerted effort to develop inhibitors specific for virally encoded enzymes. We demonstrate that 2-C-methyl ribonucleosides are efficient chain-terminating inhibitors of HCV genome replication. Characterization of drug-resistant HCV replicons defined a single S282T mutation within the active site of the viral polymerase that conferred loss of sensitivity to structurally related compounds in both replicon and isolated polymerase assays. Biochemical analyses demonstrated that resistance at the level of the enzyme results from a combination of reduced affinity of the mutant polymerase for the drug and an increased ability to extend the incorporated nucleoside analog. Importantly, the combination of these agents with interferon-␣ results in synergistic inhibition of HCV genome replication in cell culture. Furthermore, 2-C-methyl-substituted ribonucleosides also inhibited replication of genetically related viruses such as bovine diarrhea virus, yellow fever, and West African Nile viruses. These observations, together with the finding that 2-C-methyl-guanosine in particular has a favorable pharmacological profile, suggest that this class of compounds may have broad utility in the treatment of HCV and other flavivirus infections. Hepatitis C virus (HCV)1 is the most common blood-borne infection and a major cause of chronic liver disease and liver transplantation in industrialized countries. The prevalence of HCV infection is estimated to be ϳ5-fold greater than HIV infection and ranges from 1-5% in most developed countries (1). Current therapy is both poorly tolerated and has limited efficacy, with less than 50% response rates among patients infected with the most prevalent virus genotype (1b) (1). Currently approved drugs for the treatment of hepatitis C are interferon-␣ and ribavirin, neither of which appears to act directly on the virus, and their antiviral effects appear to be mediated by multiple, indirect mechanisms. Therefore, there is a need for more efficient and better tolerated anti-HCV agents.The success of antiviral therapies based on chemotherapeutic agents targeting viral polymerases has prompted intense efforts to develop inhibitors of HCV NS5B, the virally encoded RNA-dependent RNA polymerase (RdRp). Studies with HIV reverse transcriptase validate the clinical utility of two distinct classes of viral polymerase inhibitors, nucleoside and non-nucleoside inhibitors. Nucleoside inhibitors function as competitive substrate analogs that prevent RNA chain elongation when incorporated by the viral enzyme, resulting in premature chain termination (2, 3). HIV reverse transcriptase non-nucleoside inhibitors bind to a site residing outside the enzyme active site and inhibit catalysis by an allosteric mechanism (4, 5). Several putative allosteric binding sites on the surface of HCV NS5B have been suggested based on recent structural studies (6 -8), and several chemical classes of NS5B non-nucleoside inhibitors have ...

The RNA-dependent RNA polymerase (NS5B) of hepatitis C virus (HCV) is essential for the replication of viral RNA and thus constitutes a valid target for the chemotherapeutic intervention of HCV infection. In this report, we describe the identification of 2-substituted nucleosides as inhibitors of HCV replication. The 5-triphosphates of 2-C-methyladenosine and 2-O-methylcytidine are found to inhibit NS5B-catalyzed RNA synthesis in vitro, in a manner that is competitive with substrate nucleoside triphosphate. NS5B is able to incorporate either nucleotide analog into RNA as determined with gel-based incorporation assays but is impaired in its ability to extend the incorporated analog by addition of the next nucleotide. In a subgenomic replicon cell line, 2-C-methyladenosine and 2-O-methylcytidine inhibit HCV RNA replication. The 5-triphosphates of both nucleosides are detected intracellularly following addition of the nucleosides to the media. However, significantly higher concentrations of 2-C-methyladenosine triphosphate than 2-O-methylcytidine triphosphate are detected, consistent with the greater potency of 2-C-methyladenosine in the replicon assay, despite similar inhibition of NS5B by the triphosphates in the in vitro enzyme assays. Thus, the 2-modifications of natural substrate nucleosides transform these molecules into potent inhibitors of HCV replication. Hepatitis C virus (HCV)1 infection is the leading cause of sporadic, post-transfusion, non-A non-B hepatitis (1, 2). One hundred seventy million people worldwide are thought to be infected with hepatitis C virus of which an estimated 4 million reside in the United States (3). Approximately 80% of infected individuals progress to chronic infection. Long term chronic HCV infection can lead to liver cirrhosis and to hepatocellular carcinoma (4 -6). Currently, the recommended therapy is treatment with a combination of interferon ␣2b and ribavirin, which results in a sustained viral response in 40% of patients (7,8). Investigational therapies using a combination of pegylated interferon and ribavirin have lead to an sustained viral response in 54% of patients, but the response rate (42%) of patients harboring HCV genotype 1 is lower (9, 10). Consequently, additional therapies for HCV infection are needed.Antiviral chemotherapies based on administration of analogs of deoxynucleosides have been widely successful as treatment for HIV, herpes virus, and hepatitis B infection (11,12). Intracellular phosphorylation of the nucleoside analog to the triphosphate creates the active form of the inhibitor that then serves as a substrate for the viral polymerase. Generally, incorporation of the nucleotide analog at the 3Ј-end of the replicating viral DNA causes termination of DNA synthesis, owing to the lack of the 3Ј-hydroxyl required for extension. These successes suggest that an investigation of ribonucleoside analogs as inhibitors of HCV replication would be worthwhile.The HCV NS5B protein, the RNA-dependent polymerase responsible for the synthesis of the viral RNA geno...

We present a comprehensive analysis of all ring systems (both heterocyclic and nonheterocyclic) in clinical trial compounds and FDA-approved drugs. We show 67% of small molecules in clinical trials comprise only ring systems found in marketed drugs, which mirrors previously published findings for newly approved drugs. We also show there are approximately 450 000 unique ring systems derived from 2.24 billion molecules currently available in synthesized chemical space, and molecules in clinical trials utilize only 0.1% of this available pool. Moreover, there are fewer ring systems in drugs compared with those in clinical trials, but this is balanced by the drug ring systems being reused more often. Furthermore, systematic changes of up to two atoms on existing drug and clinical trial ring systems give a set of 3902 future clinical trial ring systems, which are predicted to cover approximately 50% of the novel ring systems entering clinical trials.