Lack of Detection of the Analgesic Properties of PF-05089771, a Selective Na 1.7 Inhibitor, Using a Battery of Pain Models in Healthy Subjects.

Sodium channel blockers are used for the treatment of pain, but this is limited by the lack of selectivity for different sodium channel subtypes, which can result in central nervous system and cardiovascular side effects. As such, there is special interest in the Na 1.7 subtype, which is expressed predominantly in nociceptive and sympathetic neurons.

Analgesic potential of PF-06372865, an α2/α3/α5 subtype-selective GABA partial agonist, in humans.

Background: This study investigated the analgesic effects of two doses (15 and 65 mg) of PF-06372865, a novel α2/α3/α5 gamma-aminobutyric acid A (GABA) subunit selective partial positive allosteric modulator (PAM), compared with placebo and pregabalin (300 mg) as a positive control.

Methods: We performed a randomised placebo-controlled crossover study (NCT02238717) in 20 healthy subjects, using a battery of pain tasks (electrical, pressure, heat, cold and inflammatory pain, including a paradigm of conditioned pain modulation). Pharmacodynamic measurements were performed at baseline and up to 10 h after dose.

Photosensitive epilepsy: Robust clinical efficacy of a selective GABA potentiator.

Objective: The objective of this phase 2a study was to assess the activity of PF-06372865, a positive allosteric modulator (PAM) of α2/3/5 subunit-containing GABA receptors with minimal activity at α1-containing receptors, which are believed to mediate many of the adverse events associated with benzodiazepines, in the epilepsy photosensitivity model as a proof-of-principle of efficacy.

Methods: Seven participants with a photoparoxysmal response to intermittent photic stimulation (IPS) at baseline were randomized in a double-blind, 4-period cross-over study examining single doses of 17.5 and 52.

Reproducibility of a battery of human evoked pain models to detect pharmacological effects of analgesic drugs.

Background: Although reproducibility is considered essential for any method used in scientific research, it is investigated only rarely; thus, strikingly little has been published regarding the reproducibility of evoked pain models involving human subjects. Here, we studied the reproducibility of a battery of evoked pain models for demonstrating the analgesic effects of two analgesic compounds.

Methods: A total of 81 healthy subjects participated in four studies involving a battery of evoked pain tests in which mechanical, thermal and electrical stimuli were used to measure pain detection and tolerance thresholds.

A randomised, placebo-controlled clinical trial with the α2/3/5 subunit selective GABAA positive allosteric modulator PF-06372865 in patients with chronic low back pain.

The effect of PF-06372865, a subtype-selective positive allosteric modulator of the γ-aminobutyric acid type A (GABAA) receptor, on chronic low back pain was investigated in a randomised, placebo- and active-controlled phase 2 clinical trial. The parallel treatment group trial consisted of a 1-week single-blind placebo run in the phase, followed by 4-week double-blind treatment. Patients were randomised to receive either PF-06372865, naproxen, or placebo twice a day for 4 weeks.

Efficacy of the Nav1.7 blocker PF-05089771 in a randomised, placebo-controlled, double-blind clinical study in subjects with painful diabetic peripheral neuropathy.

The effect of PF-05089771, a selective, peripherally restricted Nav1.7 sodium channel blocker on pain due to diabetic peripheral neuropathy was investigated in a randomised, placebo and active-controlled parallel group clinical trial (NCT02215252). A 1-week placebo-run in the period was followed by a 4-week treatment period and a 1-week placebo run-out/taper-down period.

Pharmacology in translation: the preclinical and early clinical profile of the novel α2/3 functionally selective GABA receptor positive allosteric modulator PF-06372865.

Background And Purpose: Benzodiazepines, non-selective positive allosteric modulators (PAMs) of GABA receptors, have significant side effects that limit their clinical utility. As many of these side effects are mediated by the α1 subunit, there has been a concerted effort to develop α2/3 subtype-selective PAMs.

Experimental Approach: In vitro screening assays were used to identify molecules with functional selectivity for receptors containing α2/3 subunits over those containing α1 subunits.

Demonstration of an anti-hyperalgesic effect of a novel pan-Trk inhibitor PF-06273340 in a battery of human evoked pain models.

Aim: Inhibitors of nerve growth factor (NGF) reduce pain in several chronic pain indications. NGF signals through tyrosine kinase receptors of the tropomyosin-related kinase (Trk) family and the unrelated p75 receptor. PF-06273340 is a small molecule inhibitor of Trks A, B and C that reduces pain in nonclinical models, and the present study aimed to investigate the pharmacodynamics of this first-in-class molecule in humans.

Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of Na1.7.

A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective Na1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties.

The use of a battery of pain models to detect analgesic properties of compounds: a two-part four-way crossover study.

Aim: The aim was to investigate the ability of a battery of pain models to detect analgesic properties of commonly used analgesics in healthy subjects.

Methods: The battery consisted of tests eliciting electrical, mechanical and thermal (contact heat and cold pressor)-pain and included a UVB model, the thermal grill illusion and a paradigm of conditioned pain modulation. Subjects were administered fentanyl 3 μg kg , phenytoin 300 mg, (S)-ketamine 10 mg and placebo (part I), or imipramine 100 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo (part II).

Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia.

In common with other chronic pain conditions, there is an unmet clinical need in the treatment of inherited erythromelalgia (IEM). TheSCN9Agene encoding the sodium channel Nav1.7 expressed in the peripheral nervous system plays a critical role in IEM.

Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release.

Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation.

Clinical Micro-Dose Studies to Explore the Human Pharmacokinetics of Four Selective Inhibitors of Human Nav1.7 Voltage-Dependent Sodium Channels.

Background: The emergence of genetic data linking Nav1.7 sodium channel over- and under- expression to human pain signalling has led to an interest in the treatment of chronic pain through inhibition of Nav1.7 channels.

Oral administration of PF-01247324, a subtype-selective Nav1.8 blocker, reverses cerebellar deficits in a mouse model of multiple sclerosis.

Cerebellar symptoms significantly diminish quality of life in patients with multiple sclerosis (MS). We previously showed that sodium channel Nav1.8, although normally restricted to peripheral somatosensory neurons, is upregulated in the cerebellum in MS, and that Nav1.

A novel selective and orally bioavailable Nav 1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability.

Background And Purpose: NaV 1.8 ion channels have been highlighted as important molecular targets for the design of low MW blockers for the treatment of chronic pain. Here, we describe the effects of PF-01247324, a new generation, selective, orally bioavailable Nav 1.

Estimation of binding rate constants using a simultaneous mixed-effects method: application to monoamine transporter reuptake inhibitor reboxetine.

Background And Purpose: Reboxetine is a clinically used antidepressant and is a racemic mixture of two enantiomers, SS- and RR-reboxetine. The aim of the work described in this manuscript was to determine the kinetics of binding of the RR- and SS-reboxetine to the human noradrenaline transporter (hNET).

Experimental Approach: We have applied a simultaneous mixed-effects method to the analysis of the transient kinetics of binding of SS-, RR- and racemic reboxetine to hNET.

Potent and selective nonpeptidic inhibitors of procollagen C-proteinase.

6-Cyclohexyl-N-hydroxy-3-(1,2,4-oxadiazol-5-yl)hexanamides were previously disclosed as inhibitors of procollagen C-proteinase (PCP) culminating in the identification of amide 1. Our objective was to discover a second inhibitor that would have improved affinity for PCP and to optimize properties for transepidermal delivery (TED) to intact skin. Further investigation of this template identified a number of potent PCP inhibitors (IC50 values of 2-6 nM) with improved TED flux.

Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines.

1-isoquinolinylguanidines were previously disclosed as potent and selective inhibitors of urokinase-type plasminogen activator (uPA). Further investigation of this template has revealed that incorporation of a 7-sulfonamide group furnishes a new series of potent and highly selective uPA inhibitors. Potency and selectivity can be achieved with sulfonamides derived from a variety of amines and is further enhanced by the incorporation of sulfonamides derived from amino acids.

Inhibition of procollagen C-proteinase reduces scar hypertrophy in a rabbit model of cutaneous scarring.

Hypertrophic scarring, which results from excessive collagen deposition at sites of dermal wound repair, can be functionally and cosmetically debilitating to the surgical patient. Pharmacological regulation of collagen synthesis and deposition is a direct approach to the control of scar tissue formation. One of the key steps in collagen stabilization is the cleavage of the C-terminal propeptide from the precursor molecule to form collagen fibrils, a reaction catalyzed by procollagen C-proteinase (PCP).

A comparative study of the structure of human and murine greater omentum.

In humans, the greater omentum is a fatty peritoneal fold that extends from the greater curvature of the stomach to cover most abdominal organs. It performs many functions, which include acting as a reservoir of resident peritoneal inflammatory cells, a storage site for lipid, and a regulator of fluid exchange in and out of the peritoneal cavity. Most importantly, the omentum readily adheres to areas of inflammation and peritoneal damage, often leading to adhesion formation.

Increased skin collagen extractability and proportions of collagen type III are not normalized after 6 months healing of human excisional wounds.

In an attempt to identify potential staging markers of effective healing, changes in connective tissue properties were measured in a human skin excisional wound healing model in which tissue was re-excised at intervals up to 6 months after injury. The proportion of collagen III relative to collagen I increased significantly (p<0.001) up to 6 weeks after initial injury and remained elevated up to 6 months, at which time the proportion of collagen III was 70% above baseline values.