A next generation peripherally restricted Cavα2δ-1 ligand with inhibitory action on Cav2.2 channels and utility in neuropathic pain.

The Voltage-Gated Calcium Channel (VGCC) auxiliary subunit Cavα2δ-1 (CACNA2D1) is the target/receptor of gabapentinoids which are known therapeutics in epilepsy and neuropathic pain. Following damage to the peripheral sensory nervous system, Cavα2δ-1 is upregulated in dorsal root ganglion (DRG) neurons in several animal models of chronic neuropathic pain. Gabapentinoids, such as gabapentin and pregabalin, engage with Cavα2δ-1 via binding an arginine residue (R241) within an RRR motif located at the N-terminus of human Cavα2δ-1. A novel, next generation gabapentinoid, engineered not to penetrate the brain, was able to generate a strong analgesic response in Chronic Constriction Injury animal model of chronic neuropathic pain and showed binding specificity for Cavα2δ-1 versus the Cavα2δ-2 subunit. This novel non-brain penetrant gabapentinoid, binds to R241 and a novel binding site on Cavα2δ-1, which is located within the VGCC_α2 domain, identified as a lysine residue within an IKAK amino acid motif (K634). The overall whole cell current amplitudes were diminished by the compound, with these inhibitory effects being diminished in R241A mutant Cavα2δ-1 subunits. The functional effects occurred at lower concentrations than those needed for inhibition by gabapentin or pregabalin, which apparently bound the Cavα2δ-1 subunit only on the R241 and not on the K634 residue. Our work sets the stage for the identification and characterisation of novel compounds with therapeutic properties in neuropathic pain and possibly in other disorders and conditions which require engagement of the Cavα2δ-1 target.

From UTP to AR-C118925, the discovery of a potent non nucleotide antagonist of the P2Y2 receptor.

The G protein-coupled P2Y2 receptor, activated by ATP and UTP has been reported as a potential drug target for a wide range of important clinical conditions, such as tumor metastasis, kidney disorders, and in the treatment of inflammatory conditions. However, pharmacological studies on this receptor have been impeded by the limited reported availability of stable, potent and selective P2Y2R antagonists. This article describes the design and synthesis of AR-C118925, a potent and selective non-nucleotide antagonist of the P2Y2 receptor discovered using the endogenous P2Y2R agonist UTP as the chemical starting point.

Discovery and evaluation of a novel monocyclic series of CXCR2 antagonists.

Antagonism of the chemokine receptor CXCR2 has been proposed as a strategy for the treatment of inflammatory diseases such as arthritis, chronic obstructive pulmonary disease and asthma. Earlier series of bicyclic CXCR2 antagonists discovered at AstraZeneca were shown to have low solubility and poor oral bioavailability. In this Letter we describe the design, synthesis and characterisation of a new series of monocyclic CXCR2 antagonists with improved solubility and good pharmacokinetic profiles.

Identification of a putative intracellular allosteric antagonist binding-site in the CXC chemokine receptors 1 and 2.

The chemokine receptors CXCR1 and CXCR2 are G-protein-coupled receptors (GPCRs) implicated in mediating cellular functions associated with the inflammatory response. Potent CXCR2 receptor antagonists have been discovered, some of which have recently entered clinical development. The aim of this study was to identify key amino acid residue differences between CXCR1 and CXCR2 that influence the relative antagonism by two compounds that have markedly different chemical structures. By investigating the effects of domain switching and point mutations, we found that the second extracellular loop, which contained significant amino acid sequence diversity, was not important for compound antagonism. We were surprised to find that switching the intracellular C-terminal 60 amino acid domains of CXCR1 and CXCR2 caused an apparent reversal of antagonism at these two receptors. Further investigation showed that a single amino acid residue, lysine 320 in CXCR2 and asparagine 311 in CXCR1, plays a predominant role in describing the relative antagonism of the two compounds. Homology modeling studies based on the structure of bovine rhodopsin indicated a potential intracellular antagonist binding pocket involving lysine 320. We conclude that residue 320 in CXCR2 forms part of a potential allosteric binding pocket on the intracellular side of the receptor, a site that is distal to the orthosteric site commonly assumed to be the location of antagonist binding to GPCRs. The existence of a common intracellular allosteric binding site at GPCRs related to CXCR2 may be of value in the design of novel antagonists for therapeutic intervention.

Novel N-aryl and N-heteroaryl sulfamide synthesis via palladium cross coupling.

A novel and efficient synthesis of N-aryl and N-heteroaryl sulfamides via an intermolecular palladium-catalyzed coupling process has been developed. The reactions proceeded with good to excellent yields and were tolerant of a wide range of functional groups. [reaction: see text]

New Lewis-basic N-oxides as chiral organocatalysts in asymmetric allylation of aldehydes.

Allylation of aromatic and heteroaromatic aldehydes 1a-k with allyltrichlorosilane 2 can be catalyzed by the new heterobidentate, terpene-derived bipyridine N-monoxides 4, 6a,b, and 8-11 (

Synthesis of new chiral 2,2'-bipyridine ligands and their application in copper-catalyzed asymmetric allylic oxidation and cyclopropanation.

A series of modular bipyridine-type ligands 1 and 3-9 has been synthesized via a de novo construction of the pyridine nucleus. The chiral moieties of these ligands originate from the isoprenoid chiral pool, namely, beta-pinene (10 --> 1), 3-carene (14 --> 3 and 5), 2-carene (28 --> 4), alpha-pinene (43 --> 6-8), and dehydropregnenolone acetate (48 --> 9), respectively. Copper(I) complexes, derived from these ligands and (TfO)(2)Cu (1 mol %) upon an in situ reduction with phenylhydrazine, exhibit good enantioselectivity (up to 82% ee) and unusually high reaction rate (typicaly 30 min at room temperature) in allylic oxidation of cyclic olefins (52 --> 53). Copper-catalyzed cyclopropanation proceeded with < or =76% enantioselectivity and approximately 3:1 to 99:1 trans/cis-diastereoselectivity (54 --> 55 + 56). The level of the asymmetric induction is discussed in terms of the ligand architecture that controls the stereochemical environment of the coordinated metal.

Chiral 2,2'-bipyridine-type N-monoxides as organocatalysts in the enantioselective allylation of aldehydes with allyltrichlorosilane.

[reaction: see text] The Sakurai-Hosomi-type allylation of aromatic and heteroaromatic aldehydes can be catalyzed by the new heterobidenate bipyridine monoxide PINDOX with high enantioselectivities. The sterochemical outcome is mainly controlled by the axial chirality in PINDOX, which in turn is determined by the annulated terpene units.