Evaluating disease control following belimumab treatment in patients with SLE enrolled in the US OBSErve study.

OBJECTIVE: To characterise disease control and remission in patients with SLE receiving belimumab for up to 12 months in the real world. METHODS: This post hoc analysis (GSK Study 213502) used data from the US evaluation Of use of Belimumab in clinical practice SEttings (OBSErve) study (GSK Study 117295), an observational cohort study of adults with SLE initiating and continuing belimumab for ≥6 months. Data were collected every 6 months by physician chart review; details of disease activity using the Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score were collected if routinely used by physicians. Disease control definitions evaluated were SELENA-SLEDAI score of ≤2 at 12 months, SELENA-SLEDAI score of ≤2 and glucocorticoid (prednisone equivalent) dose of ≤5 mg/day at 12 months, SELENA-SLEDAI score of ≤2 and glucocorticoid dose of ≤5 mg/day at both 6 and 12 months. Disease remission definition was SELENA-SLEDAI score=0 at 12 months. Glucocorticoid dose during follow-up was quantified. RESULTS: US OBSErve enrolled 501 patients, 90 of whom had eligible SELENA-SLEDAI scores for inclusion in this analysis. Mean (SD) SELENA-SLEDAI scores were 13.1 (3.0) at baseline and 4.9 (3.4) at 12 months. Disease control at 12 months was achieved by 31.1% of patients when defined as a SELENA-SLEDAI score of ≤2 (95% CI 21.8 to 41.7); this decreased to 25.6% when requiring a SELENA-SLEDAI score of ≤2 and glucocorticoid dose of ≤5 mg/day (95% CI 16.9 to 35.8) and 17.8% when requiring a SELENA-SLEDAI score of ≤2 and glucocorticoid dose of ≤5 mg/day at both 6 and 12 months (95% CI 10.5 to 27.3). No patient achieved remission at 12 months. Glucocorticoids decreased from a baseline median of 20.0 mg/day (IQR 15.0-30.0) to 5.0 mg/day (IQR 0-10.0) at 12 months. CONCLUSION: Improved disease control and reduced glucocorticoid use was achieved for a proportion of patients following up to 12 months of belimumab treatment in a US real-world setting.

Benzoxazolinone aryl sulfonamides as potent, selective Nav1.7 inhibitors with in vivo efficacy in a preclinical pain model.

Studies on human genetics have suggested that inhibitors of the Nav1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Nav1.7 inhibitors with excellent selectivity against the Nav1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Nav1.5 exceeding 1000-fold. Key structure-activity relationships associated with oral bioavailability were leveraged to discover compound 17, which exhibited a comparable potency/selectivity profile as well as full efficacy following oral administration in a preclinical model indicative of antinociceptive behavior.

Discovery of a pharmacologically active antagonist of the two-pore-domain potassium channel K2P9.1 (TASK-3).

TWIK-related acid-sensitive K(+) (K(2P) 9.1, TASK-3) ion channels have the capacity to regulate the activity of neuronal pathways by influencing the resting membrane potential of neurons on which they are expressed. The central nervous system (CNS) expression of these channels suggests potential roles in neurologic disorders, and it is believed that the development of TASK-3 antagonists could lead to the therapeutic treatment of a number of neurological conditions. While a therapeutic potential for TASK-3 channel modulation exists, there are only a few documented examples of potent and selective small-molecule channel blockers. Herein, we describe the discovery and lead optimization efforts for a novel series of TASK-3 channel antagonists based on a 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine high-throughput screening lead from which a subseries of potent and selective inhibitors were identified. One compound was profiled in detail with respect to its physical properties and demonstrated pharmacological target engagement as indicated by its ability to modulate sleep architecture in rodent electroencephalogram (EEG) telemetry models.

In vitro characterization of T-type calcium channel antagonist TTA-A2 and in vivo effects on arousal in mice.

T-type calcium channels have been implicated in many behaviorally important neurophysiological processes, and altered channel activity has been linked to the pathophysiology of neurological disorders such as insomnia, epilepsy, Parkinson's disease, depression, schizophrenia, and pain. We have previously identified a number of potent and selective T-type channel antagonists (Barrow et al., 2007; Shipe et al., 2008; Yang et al., 2008). Here we describe the properties of the antagonist TTA-A2 [2-(4-cyclopropylphenyl)-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)oxo]-pyridin-2-yl}ethyl)acetamide], assessed in patch-clamp experiments. TTA-A2 blocks T-type channels (Ca(v)3.1, 3.2, 3.3) voltage dependently and with high potency (IC(50) ∼100 nM). Stimulation at 3 Hz revealed additional use dependence of inhibition. A hyperpolarized shift of the channel availability curve and delayed channel recovery from inactivation suggest that the compound preferentially interacts with and stabilizes inactivated channels. The compound showed a ∼300-fold selectivity for Ca(v)3 channels over high-voltage activated calcium channels. Inhibitory effects on native T-type currents were confirmed in brain slice recordings from the dorsal lateral geniculate nucleus and the subthalamic nucleus. Furthermore, we demonstrate that in vivo T-type channel inhibition by TTA-A2 suppresses active wake and promotes slow-wave sleep in wild-type mice but not in mice lacking both Ca(v)3.1 and Ca(v)3.3, suggesting the selective effect of TTA-A2 on recurrent thalamocortical network activity. The discovery of the potent and selective T-type channel antagonist TTA-A2 has enabled us to study the in vivo effects of pharmacological T-channel inhibition on arousal in mice, and it will help to explore the validity of these channels as potential drug targets for sleep-related and other neurological diseases.