PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice

The role of protein-tyrosine phosphatase 1B (PTP1B) in diabetes was investigated using an antisense oligonucleotide in ob/ob and db/db mice. PTP1B antisense oligonucleotide treatment normalized plasma glucose levels, postprandial glucose excursion, and HbA(1C). Hyperinsulinemia was also reduced with improved insulin sensitivity. PTP1B protein and mRNA were reduced in liver and fat with no effect in skeletal muscle. Insulin signaling proteins, insulin receptor substrate 2 and phosphatidylinositol 3 (PI3)-kinase regulatory subunit p50α, were increased and PI3-kinase p85α expression was decreased in liver and fat. These changes in protein expression correlated with increased insulin-stimulated protein kinase B phosphorylation. The expression of liver gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, and fructose-1,6-bisphosphatase was also down-regulated. These findings suggest that PTP1B modulates insulin signaling in liver and fat, and that therapeutic modalities targeting PTP1B inhibition may have clinical benefit in type 2 diabetes

Substituted Indazoles as Na_v1.7 Blockers for the Treatment of Pain

The genetic validation for the role of the Na_v1.7 voltage-gated ion channel in pain signaling pathways makes it an appealing target for the potential development of new pain drugs. The utility of nonselective Na_v blockers is often limited due to adverse cardiovascular and CNS side effects. We sought more selective Na_v1.7 blockers with oral activity, improved selectivity, and good druglike properties. The work described herein focused on a series of 3- and 4-substituted indazoles. SAR studies of 3-substituted indazoles yielded analog <b>7</b> which demonstrated good in vitro and in vivo activity but poor rat pharmacokinetics. Optimization of 4-substituted indazoles yielded two compounds, <b>27</b> and <b>48</b>, that exhibited good in vitro and in vivo activity with improved rat pharmacokinetic profiles. Both <b>27</b> and <b>48</b> demonstrated robust activity in the acute rat monoiodoacetate-induced osteoarthritis model of pain, and subchronic dosing of <b>48</b> showed a shift to a lower EC₅₀ over 7 days

Substituted Indazoles as Na_v1.7 Blockers for the Treatment of Pain

The genetic validation for the role of the Na_v1.7 voltage-gated ion channel in pain signaling pathways makes it an appealing target for the potential development of new pain drugs. The utility of nonselective Na_v blockers is often limited due to adverse cardiovascular and CNS side effects. We sought more selective Na_v1.7 blockers with oral activity, improved selectivity, and good druglike properties. The work described herein focused on a series of 3- and 4-substituted indazoles. SAR studies of 3-substituted indazoles yielded analog <b>7</b> which demonstrated good in vitro and in vivo activity but poor rat pharmacokinetics. Optimization of 4-substituted indazoles yielded two compounds, <b>27</b> and <b>48</b>, that exhibited good in vitro and in vivo activity with improved rat pharmacokinetic profiles. Both <b>27</b> and <b>48</b> demonstrated robust activity in the acute rat monoiodoacetate-induced osteoarthritis model of pain, and subchronic dosing of <b>48</b> showed a shift to a lower EC₅₀ over 7 days

P2X receptor antagonists for pain management: examination of binding and physicochemical properties

Enhanced sensitivity to noxious stimuli and the perception of non-noxious stimuli as painful are hallmark sensory perturbations associated with chronic pain. It is now appreciated that ATP, through its actions as an excitatory neurotransmitter, plays a prominent role in the initiation and maintenance of chronic pain states. Mechanistically, the ability of ATP to drive nociceptive sensitivity is mediated through direct interactions at neuronal P2X3 and P2X2/3 receptors. Extracellular ATP also activates P2X4, P2X7, and several P2Y receptors on glial cells within the spinal cord, which leads to a heightened state of neural-glial cell interaction in ongoing pain states. Following the molecular identification of the P2 receptor superfamilies, selective small molecule antagonists for several P2 receptor subtypes were identified, which have been useful for investigating the role of specific P2X receptors in preclinical chronic pain models. More recently, several P2X receptor antagonists have advanced into clinical trials for inflammation and pain. The development of orally bioavailable blockers for ion channels, including the P2X receptors, has been traditionally difficult due to the necessity of combining requirements for target potency and selectivity with suitable absorption distribution, metabolism, and elimination properties. Recent studies on the physicochemical properties of marketed orally bioavailable drugs, have identified several parameters that appear critical for increasing the probability of achieving suitable bioavailability, central nervous system exposure, and acceptable safety necessary for clinical efficacy. This review provides an overview of the antinociceptive pharmacology of P2X receptor antagonists and the chemical diversity and drug-like properties for emerging antagonists of P2X3, P2X2/3, P2X4, and P2X7 receptors