A channel involved in pain perception Voltage-gated sodium (Nav) channels propagate electrical signals in muscle cells and neurons. In humans, Nav1.7 plays a key role in pain perception. It is challenging to target a particular Nav isoform; however, arylsulfonamide antagonists selective for Nav1.7 have been reported recently. Ahuja et al. characterized the binding of these small molecules to human Nav channels. To further investigate the mechanism, they engineered a bacterial Nav channel to contain features of the Nav1.7 voltage-sensing domain that is targeted by the antagonist and determined the crystal structure of the chimera bound to an inhibitor. The structure gives insight into the mechanism of voltage sensing and will enable the design of more-selective Nav channel antagonists. Science , this issue p. 10.1126/science.aac5464

The mild and selective hydrolysis of esters can often be crucial in the sequence toward a target molecule and is, therefore, an important objective in contemporary organic synthesis. Although several methods exist to accomplish this task in certain cases, a mild, generally applicable protocol remains absent. Frequent problems encountered include the concurrent hydrolysis of other ester groups present within the molecule under scrutiny, epimerization of stereocenters, and elimination reactions induced by the often basic conditions employed. Herein we report a new and selective method for the hydrolysis of esters under extremely mild conditions that avoid such side reactions and lead to high yields of the corresponding carboxylic acids.It was during our campaign toward thiostrepton, [1] a highly complex thiopeptide antibiotic, that we had the opportunity to search for such a method. Our sensitive intermediates proved too fragile to tolerate standard ester hydrolysis conditions. We finally came upon Me 3 SnOH, which had been previously employed by Mascaretti and co-workers [2] to cleave phenacyl ester anchored amino acids and peptides from a polystyrene resin and to hydrolyze methyl and isopropyl phenylacetate to give the corresponding acids in high yield. To our knowledge, these are the only examples in which Me 3 SnOH has been previously used to carry out hydrolytic ruptures of esters.[3] As shown in Table 1, this reagent proved extremely useful to us in attaining the highyielding and selective hydrolysis of methyl esters within the sensitive substrates 1-4, which were encountered en route to thiostrepton. These remarkable results prompted a secondphase investigation in which we attempted to determine systematically the generality and scope of this protocol, which involved heating the substrate with 1-10 equivalents of[*] Prof.

The discovery and optimization of a series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine compounds that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compounds demonstrate potent inhibition of all three Akt isoforms in biochemical assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. Biological studies with one such compound, 28 (GDC-0068), demonstrate good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway is activated. 28 is currently being evaluated in human clinical trials for the treatment of cancer.

Selective block of Na1.7 promises to produce non-narcotic analgesic activity without motor or cognitive impairment. Several Na1.7-selective blockers have been reported, but efficacy in animal pain models required high multiples of the IC for channel block. Here, we report a target engagement assay using transgenic mice that has enabled the development of a second generation of selective Nav1.7 inhibitors that show robust analgesic activity in inflammatory and neuropathic pain models at low multiples of the IC. Like earlier arylsulfonamides, these newer acylsulfonamides target a binding site on the surface of voltage sensor domain 4 to achieve high selectivity among sodium channel isoforms and steeply state-dependent block. The improved efficacy correlates with very slow dissociation from the target channel. Chronic dosing increases compound potency about 10-fold, possibly due to reversal of sensitization arising during chronic injury, and provides efficacy that persists long after the compound has cleared from plasma.

The first phase of the total synthesis of thiostrepton (1), a highly complex thiopeptide antibiotic, is described. After a brief introduction to the target molecule and its structural motifs, it is shown that retrosynthetic analysis of thiostrepton reveals compounds 23, 24, 26, 28, and 29 as potential key building blocks for the projected total synthesis. Concise and stereoselective constructions of all these intermediates are then described. The synthesis of the dehydropiperidine core 28 was based on a biosynthetically inspired aza-Diels-Alder dimerization of an appropriate azadiene system, an approach that was initially plagued with several problems which were, however, resolved satisfactorily by systematic investigations. The quinaldic acid fragment 24 and the thiazoline-thiazole segment 26 were synthesized by a series of reactions that included asymmetric and other stereoselective processes. The dehydroalanine tail precursor 23 and the alanine equivalent 29 were also prepared from the appropriate amino acids. Finally, a method was developed for the direct coupling of the labile dehydropiperidine key building block 28 to the more advanced and stable peptide intermediate 27 through capture with the highly reactive alanine equivalent 67 under conditions that avoided the initially encountered destructive ring contraction process.

No abstract

The mild and selective hydrolysis of esters can often be crucial in the sequence toward a target molecule and is, therefore, an important objective in contemporary organic synthesis. Although several methods exist to accomplish this task in certain cases, a mild, generally applicable protocol remains absent. Frequent problems encountered include the concurrent hydrolysis of other ester groups present within the molecule under scrutiny, epimerization of stereocenters, and elimination reactions induced by the often basic conditions employed. Herein we report a new and selective method for the hydrolysis of esters under extremely mild conditions that avoid such side reactions and lead to high yields of the corresponding carboxylic acids.It was during our campaign toward thiostrepton, [1] a highly complex thiopeptide antibiotic, that we had the opportunity to search for such a method. Our sensitive intermediates proved too fragile to tolerate standard ester hydrolysis conditions. We finally came upon Me 3 SnOH, which had been previously employed by Mascaretti and co-workers [2] to cleave phenacyl ester anchored amino acids and peptides from a polystyrene resin and to hydrolyze methyl and isopropyl phenylacetate to give the corresponding acids in high yield. To our knowledge, these are the only examples in which Me 3 SnOH has been previously used to carry out hydrolytic ruptures of esters.[3] As shown in Table 1, this reagent proved extremely useful to us in attaining the highyielding and selective hydrolysis of methyl esters within the sensitive substrates 1-4, which were encountered en route to thiostrepton. These remarkable results prompted a secondphase investigation in which we attempted to determine systematically the generality and scope of this protocol, which involved heating the substrate with 1-10 equivalents of[*] Prof.

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.