RNA polymerases effectively discriminate against deoxyribonucleotides and specifically recognize ribonucleotide substrates most likely through direct hydrogen bonding interaction with the 2-␣-hydroxy moieties of ribonucleosides. Therefore, ribonucleoside analogs as inhibitors of viral RNA polymerases have mostly been designed to retain hydrogen bonding potential at this site for optimal inhibitory potency. Here, two novel nucleoside triphosphate analogs are described, which are efficiently incorporated into nascent RNA by the RNA-dependent RNA polymerase NS5B of hepatitis C virus (HCV), causing chain termination, despite the lack of ␣-hydroxy moieties. 2-Deoxy-2-␤-fluoro-4-azidocytidine (RO-0622) and 2-deoxy-2-␤-hydroxy-4-azidocytidine (RO-9187) were excellent substrates for deoxycytidine kinase and were phosphorylated with efficiencies up to 3-fold higher than deoxycytidine. As compared with previous reports on ribonucleosides, higher levels of triphosphate were formed from RO-9187 in primary human hepatocytes, and both compounds were potent inhibitors of HCV virus replication in the replicon system (IC 50 ‫؍‬ 171 ؎ 12 nM and 24 ؎ 3 nM for RO-9187 and RO-0622, respectively; CC 50 >1 mM for both). Both compounds inhibited RNA synthesis by HCV polymerases from either HCV genotypes 1a and 1b or containing S96T or S282T point mutations with similar potencies, suggesting no cross-resistance with either R1479 (4-azidocytidine) or 2-C-methyl nucleosides. Pharmacokinetic studies with RO-9187 in rats and dogs showed that plasma concentrations exceeding HCV replicon IC 50 values 8 -150-fold could be achieved by low dose (10 mg/kg) oral administration. Therefore, 2-␣-deoxy-4-azido nucleosides are a new class of antiviral nucleosides with promising preclinical properties as potential medicines for the treatment of HCV infection. Hepatitis C virus (HCV)3 infection is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma and is the leading cause of liver transplantation. Current treatment options available to HCV-infected persons have limitations with regard to efficacy and tolerability. Only about 50% of individuals infected with HCV genotype 1 achieve sustained virological response when treated with a combination of pegylated interferon ␣ and ribavirin (1, 2). In addition, high viral load, age, body weight, co-infection with human immunodeficiency virus, and cirrhosis negatively affect the probability of achieving sustained virological response (3, 4). Therefore, there is an urgent need to develop new and more effective therapies for the treatment of HCV infection. A number of new antiviral candidates are currently being evaluated in clinical studies, the majority targeting either the HCV protease or HCV polymerase enzymes, which are essential for viral replication (5). The HCV RNA-dependent RNA polymerase, NS5B, contains the active site responsible for viral RNA synthesis and functions as part of a membrane-associated replicase complex. Nucleoside and non-nucleoside inhibitors of HCV polymerase h...

Baclofen is a racemic GABA B receptor agonist that has a number of significant pharmacokinetic limitations, including a narrow window of absorption in the upper small intestine and rapid clearance from the blood. Arbaclofen placarbil is a novel transported prodrug of the pharmacologically active R-isomer of baclofen designed to be absorbed throughout the intestine by both passive and active mechanisms via the monocarboxylate type 1 transporter. Arbaclofen placarbil is rapidly converted to R-baclofen in human and animal tissues in vitro. This conversion seems to be primarily catalyzed in human tissues by human carboxylesterase-2, a major carboxylesterase expressed at high levels in various tissues including human intestinal cells. Arbaclofen placarbil was efficiently absorbed and rapidly converted to R-baclofen after oral dosing in rats, dogs, and monkeys. Exposure to R-baclofen was proportional to arbaclofen placarbil dose, whereas exposure to intact prodrug was low. Arbaclofen placarbil demonstrated enhanced colonic absorption, i.e., 5-fold higher R-baclofen exposure in rats and 12-fold higher in monkeys compared with intracolonic administration of R-baclofen. Sustained release formulations of arbaclofen placarbil demonstrated sustained R-baclofen exposure in dogs with bioavailability up to 68%. In clinical use, arbaclofen placarbil may improve the treatment of patients with gastroesophageal reflux disease, spasticity, and numerous other conditions by prolonging exposure and decreasing the fluctuations in plasma levels of R-baclofen.

Background: The small molecule CCX559 is a novel, highly potent inhibitor of human PD-L1 being developed as an oral treatment for cancer patients. We have previously demonstrated that CCX559 has nanomolar potency and high selectivity for PD-L1; that it enhances primary T cell activation and has anti-tumor efficacy, including the ability to induce complete responses, using in vivo models1. Results: Safety pharmacology studies in preclinical animal species demonstrated pharmacokinetics and an acceptable safety profile for CCX559, which supported the initiation of human trials in patients with advanced tumors. Prior findings from toxicology studies were consistent with immune modulation, including consumptive coagulopathy, increased white blood cell counts, and changes in IL-6 plasma levels. A Phase 1, first in patient, multicenter, open-label, dose-escalation study was initiated, with a starting dose of once-daily (QD) oral dosing at 30 mg. The primary objectives are safety/tolerability, as well pharmacokinetic (PK) assessments aimed at determining a future phase 2 dose. Secondary objectives include pharmacodynamic (PD) assessments of immune cell activation in patient peripheral blood samples, as well as anti-tumor effects. For PK, intensive blood sampling is done on day 1 and day 21 of the first cycle of dosing; additional samples are collected on select days throughout the 21-day treatment cycles. PD analyses are done on selected blood draws as well. The first patient dosed (30 mg QD) showed that the drug was well tolerated with no adverse events reported. Preliminary PK results from this patient revealed CCX559 exposure levels consistent with preclinical predictions. Moreover, PD samples showed elevations in T cell proliferation and activation within the first 15 days, when compared to the predose sample. In conclusion, the preclinical data support clinical development of CCX559. CCX559 shows encouraging initial PK and PD results, and patient enrollment is ongoing in the trial (ACTRN12621001342808). References: 1Chris Li, et al. CCX559 is a potent orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1274. Citation Format: Kathleen M. Sullivan, Shichang Miao, Huibin Yue, Niky Zhao, Chris Li, Ezra Tai, Karen Ebsworth, Gonzalo Tapia Rico, Paul De Souza, Tom Schall, Penglie Zhang. CCX559, an orally administered small molecule PD-L1 inhibitor for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4147.