Development of well tolerated novel Inhibitors of drug resistant CMV

CMV occurs as a benign infection in most humans, with an estimated 60-90% of the population infected during their lives. However, in immunosuppressed patients, particularly in recipients of solid organ or bone marrow transplants, allogenic CMV infection is a major cause of morbidity and mortality. Approximately 30,000 solid organ transplant and 9,000 bone marrow transplants operations are performed in the U.S. every year. If untreated, primary infection and reactivation can result in CMV disease, which can affect multiple organs and require intensive care, thereby resulting in significant cost. Current FDA-approved anti-CMV drugs have significant drawbacks, including poor oral bioavailability, dose-limiting toxicity, and drug resistance. Given the impact of this virus, there is a significant need for novel well tolerated therapeutics that are active against drug- resistant strains. To address this need, we are developing a novel class of drugs that inhibit the early stage of CMV replication, which will be used for the prevention and/or treatment of CMV infections in transplant recipients. We utilized a novel human CMV reporter virus to identify MBXC-4302, a non-nucleoside N-arylpyrimidinamine (NAPA) with potent anti-CMV activity (IC50 = 3.2 µM), high selectivity (CC50/IC50 >30), and favorable in vitro ADME properties. Preliminary mechanism of action studies demonstrated that MBXC-4302 specifically inhibits CMV replication at an early stage of its lifecycle. One of the more potent compounds in the NAPA chemical series (MBX-4992) was tested against a panel of herpesviruses and was most active against human CMV (IC50 = 1.7 µM) at a potency comparable to ganciclovir (GCV, IC50 = 0.9 µM). In addition, MBX-4992 was effective against a GCV-resistant strain of human CMV (IC50 = 1.8 µM). Significantly, MBX-4992 was active against murine CMV (IC50 = 4.5 µM), enabling future in vivo efficacy studies in the murine model of CMV infection. In this Phase 1 SBIR, we will chemically optimize the activity, selectivity, and drug-like features of the NAPA hit series in an SAR-driven hit-to-lead optimization program to generate 2 – 4 lead candidates. Prioritized NAPA analogs will be further evaluated in in vitro CMV proliferation assays and in mice for tolerability and pharmacokinetic properties. A subsequent Phase 2 application will establish in vivo efficacy in CMV mouse models and evaluate tolerability with an objective to avoid toxicities associated with current approved anti-CMV drugs. The specific aims of this proposal are as follows. Aim 1: Optimize the anti-CMV activity of the NAPA series through an SAR-driven approach. Aim 2: Prioritize NAPA analogs according to their activity against drug-resistant CMV isolates, anti-CMV activity in in vitro models and bone marrow safety. Aim 3: Prioritize NAPA analogs with favorable in vitro ADME properties and establish suitable in vivo pharmacokinetics and tolerability in mice.