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Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium ion channel highly expressed in the primary sensory neurons, functioning as a polymodal sensor for exogenous and endogenous stimuli, and has been implicated in neuropathic pain and respiratory disease. Herein, we describe the optimization of potent, selective, and orally bioavailable TRPA1 small molecule antagonists with strong in vivotarget engagement in rodent models. Several lead molecules in preclinical single- and short-term repeat-dose toxicity studies exhibited profound prolongation of coagulation parameters. Based on a thorough investigative toxicology and clinical pathology analysis, anticoagulation effects in vivoare hypothesized to be manifested by a metabolite─generated by aldehyde oxidase (AO)─possessing a similar pharmacophore to known anticoagulants (i.e., coumarins, indandiones). Further optimization to block AO-mediated metabolism yielded compounds that ameliorated coagulation effects in vivo, resulting in the discovery and advancement of clinical candidate GDC-6599, currently in Phase II clinical trials for respiratory indications.

abstract:This article argues that Milton scholarship in an age of emboldened white supremacy needs to take account of Milton’s own whiteness and especially his role in the historical development of white identity. Based on a close reading of the Hamitic curse, as retold by Michael in book 12 of Paradise Lost, it argues that Milton translated the racial hierarchies of his own day into the split structure of an emergent racial liberalism. Milton remade white identity into the racially unmarked category of universal liberal personhood while carving out an exception for racially marked but strategically unspecified others who may be enslaved with “no wrong, / But justice.”

abstract:In book 8 of Paradise Lost, God ironically laments that he is "alone / From all Eternitie" (405–6), lacking an "equal" suitable for companionship. This article argues that God's provocative claim to loneliness registers a history of divine desocialization stretching from the depolytheization of the biblical and classical gods to Milton's own relentless reduction of Christianity to its monotheistic core. Milton could not have endorsed divine loneliness, but his poem thinks about it deeply nonetheless.

Among all transition metals magnetic alloys, Co35Fe65 possesses the highest saturation magnetization BS = 2.45 T at room temperature given by the so-called "Slater-Pauling limit". For controlled electrodeposition of Co35Fe65 nanowire arrays the following parameters were found to be optimal: electrolyte solution with 1-2 mM malonic acid (MA), ionic ratio Fe+2/Co+2 = 2.0, growth rate, and pulsed potential deposition with time-on (2.5 s) at the potential of [?]1.15 V/SCE and time-off (1.0 s) at [?]0.70 V/SCE. These arrays were deposited inside anodic aluminum oxide (AAO) templates that contained columnar nanopores with diameters either 35 or 200 nm. Cyclic voltammetry was used in solution with and without MA and reaction mechanism was proposed to explain the critical role of MA in electrodeposition of CoFe alloys. In addition to uniform deposition of stechiometric Co35Fe65 alloys, a selectivity ratio, (SR) [?]1.0, were achieved, which means that the atomic ratio of Fe/Co in the nanowire matched the molar ratio of Fe+2/Co+2 in the electrolyte. The magnetic behavior of the subsequent 2.45 T Co35Fe65 nanowire arrays showed that the shape and magnetostatic anisotropies dominated the effective anisotropy, and the impact of magnetocrystalline and magnetelastic anisotropies field was very small.

New reaction conditions are described that enable the direct arylation of pentafluorobenzene with sterically encumbered aryl bromides and aryl chlorides. These reactions occur in high yield and under mild conditions. Notably, the reactions can be performed at 80 °C in isopropyl acetate with a catalyst generated by the in situ mixing of Pd(OAc)2and S-Phos. The enhanced scope of these transformations should further reduce the need to use pentafluorophenylboronic acid in the construction of perfluoroarenes.

Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium-permeable ion channel highly expressed in the primary sensory neurons functioning as a polymodal sensor for exogenous and endogenous stimuli and has generated widespread interest as a target for inhibition due to its implication in neuropathic pain and respiratory disease. Herein, we describe the optimization of a series of potent, selective, and orally bioavailable TRPA1 small molecule antagonists, leading to the discovery of a novel tetrahydrofuran-based linker. Given the balance of physicochemical properties and strong in vivotarget engagement in a rat AITC-induced pain assay, compound 20was progressed into a guinea pig ovalbumin asthma model where it exhibited significant dose-dependent reduction of inflammatory response. Furthermore, the structure of the TRPA1 channel bound to compound 21was determined via cryogenic electron microscopy to a resolution of 3 Å, revealing the binding site and mechanism of action for this class of antagonists.

Among all transition metals magnetic alloys, Co35Fe65possesses the highest saturation magnetization BS= 2.45 T at room temperature given by the so-called “Slater-Pauling limit”. For controlled electrodeposition of Co35Fe65nanowire arrays the following parameters were found to be optimal: electrolyte solution with 1–2 mM malonic acid (MA), ionic ratio Fe+2/Co+2= 2.0, growth rate, and pulsed potential deposition with time-on (2.5 s) at the potential of −1.15 V/SCE and time-off (1.0 s) at −0.70 V/SCE. These arrays were deposited inside anodic aluminum oxide (AAO) templates that contained columnar nanopores with diameters either 35 or 200 nm. Cyclic voltammetry was used in solution with and without MA and reaction mechanism was proposed to explain the critical role of MA in electrodeposition of CoFe alloys. In addition to uniform deposition of stechiometric Co35Fe65alloys, a selectivity ratio, (SR) ∼1.0, were achieved, which means that the atomic ratio of Fe/Co in the nanowire matched the molar ratio of Fe+2/Co+2in the electrolyte. The magnetic behavior of the subsequent 2.45 T Co35Fe65nanowire arrays showed that the shape and magnetostatic anisotropies dominated the effective anisotropy, and the impact of magnetocrystalline and magnetelastic anisotropies field was very small.

Optimized conditions allow the reductive cyclization of various aromatic substrates bearing a wide range of functionalities.

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