Discovery of an Oral Respiratory Syncytial Virus (RSV) Fusion Inhibitor (GS-5806) and Clinical Proof of Concept in a Human RSV Challenge Study

GS-5806 is a novel, orally bioavailable RSV fusion inhibitor discovered following a lead optimization campaign on a screening hit. The oral absorption properties were optimized by converting to the pyrazolo­[1,5-<i>a</i>]-pyrimidine heterocycle, while potency, metabolic, and physicochemical properties were optimized by introducing the <i>para</i>-chloro and aminopyrrolidine groups. A mean EC₅₀ = 0.43 nM was found toward a panel of 75 RSV A and B clinical isolates and dose-dependent antiviral efficacy in the cotton rat model of RSV infection. Oral bioavailability in preclinical species ranged from 46 to 100%, with evidence of efficient penetration into lung tissue. In healthy human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a mean 4.2 log₁₀ reduction in peak viral load and a significant reduction in disease severity compared to placebo. In conclusion, a potent, once daily, oral RSV fusion inhibitor with the potential to treat RSV infection in infants and adults is reported

Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1‑<i>f</i>][triazin-4-amino] Adenine <i>C</i>‑Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses

The recent Ebola virus (EBOV) outbreak in West Africa was the largest recorded in history with over 28,000 cases, resulting in >11,000 deaths including >500 healthcare workers. A focused screening and lead optimization effort identified <b>4b</b> (GS-5734) with anti-EBOV EC₅₀ = 86 nM in macrophages as the clinical candidate. Structure activity relationships established that the 1′-CN group and <i>C</i>-linked nucleobase were critical for optimal anti-EBOV potency and selectivity against host polymerases. A robust diastereoselective synthesis provided sufficient quantities of <b>4b</b> to enable preclinical efficacy in a non-human-primate EBOV challenge model. Once-daily 10 mg/kg iv treatment on days 3–14 postinfection had a significant effect on viremia and mortality, resulting in 100% survival of infected treated animals [Nature 2016, 531, 381−385]. A phase 2 study (PREVAIL IV) is currently enrolling and will evaluate the effect of <b>4b</b> on viral shedding from sanctuary sites in EBOV survivors

Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late <i>I</i>_Nai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties

Late sodium current (late <i>I</i>_Na) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Na_v 1.5 channel, resulting in incomplete inactivation. Compound <b>4</b> (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late <i>I</i>_Na, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia–ventricular fibrillation (VT–VF). We will describe structure–activity relationship (SAR) leading to the discovery of <b>4</b> that is vastly improved from the first generation late <i>I</i>_Na inhibitor <b>1</b> (ranolazine). Compound <b>4</b> was 42 times more potent than <b>1</b> in reducing ischemic burden in vivo (S–T segment elevation, 15 min left anteriorior descending, LAD, occlusion in rabbits) with EC₅₀ values of 190 and 8000 nM, respectively. Compound <b>4</b> represents a new class of potent late <i>I</i>_Na inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients