Paul A. Glossop

Inhibition of TRPM8 channels reduces pain in the cold pressor test in humans.

The transient receptor potential (subfamily M, member 8; TRPM8) is a nonselective cation channel localized in primary sensory neurons, and is a candidate for cold thermosensing, mediation of cold pain, and bladder overactivity. Studies with TRPM8 knockout mice and selective TRPM8 channel blockers demonstrate a lack of cold sensitivity and reduced cold pain in various rodent models. Furthermore, TRPM8 blockers significantly lower body temperature. We have identified a moderately potent (IC50 = 103 nM), selective TRPM8 antagonist, PF-05105679 [(R)-3-[(1-(4-fluorophenyl)ethyl)(quinolin-3-ylcarbonyl)amino]methylbenzoic acid]. It demonstrated activity in vivo in the guinea pig bladder ice water and menthol challenge tests with an IC50 of 200 nM and reduced core body temperature in the rat (at concentrations >1219 nM). PF-05105679 was suitable for acute administration to humans and was evaluated for effects on core body temperature and experimentally induced cold pain, using the cold pressor test. Unbound plasma concentrations greater than the IC50 were achieved with 600- and 900-mg doses. The compound displayed a significant inhibition of pain in the cold pressor test, with efficacy equivalent to oxycodone (20 mg) at 1.5 hours postdose. No effect on core body temperature was observed. An unexpected adverse event (hot feeling) was reported, predominantly periorally, in 23 and 36% of volunteers (600- and 900-mg dose, respectively), which in two volunteers was nontolerable. In conclusion, this study supports a role for TRPM8 in acute cold pain signaling at doses that do not cause hypothermia.

The discovery of adamantyl-derived, inhaled, long acting β2-adrenoreceptor agonists

The design and profile of a series of adamantyl-containing long acting beta(2)-adrenoreceptor agonists are described. An optimal pharmacokinetic profile of low oral bioavailability was combined with a strong pharmacology profile when assessed using a guinea pig trachea tissue model. A focus was then placed on developing a robust synthetic route to ensure rapid delivery of material for clinical trials.

Novel Amino-pyrazole Ureas with Potent In Vitro and In Vivo Antileishmanial Activity.

Visceral leishmaniasis is a severe parasitic disease that is one of the most neglected tropical diseases. Treatment options are limited, and there is an urgent need for new therapeutic agents. Following an HTS campaign and hit optimization, a novel series of amino-pyrazole ureas has been identified with potent in vitro antileishmanial activity. Furthermore, compound 26 shows high levels of in vivo efficacy (>90%) against Leishmania infantum, thus demonstrating proof of concept for this series.

Identification of Type-II Inhibitors Using Kinase Structures.

Spleen tyrosine kinase is a non‐receptor tyrosine kinase, overactivation of which is thought to contribute to autoimmune diseases as well as allergy and asthma. Protein kinases have a highly conserved ATP binding site, thus making challenging the design of selective small molecule inhibitors. It has been well documented that some protein kinases can be stabilized in their inactive conformations (Type‐II inhibitors). Herein, we describe a protein structure/ligand‐based approach to successfully identify ligands that bind to novel conformations of spleen tyrosine kinase. By utilizing kinase protein crystal structures both in the public domain (RCSB) and within Pfizer’s protein crystal database, we report the discovery of the first spleen tyrosine kinase Type‐II ligands. Compounds 1 and 3 were found to bind to the DFG‐out conformation of spleen tyrosine kinase, while compound 2 binds to a DFG‐in, C‐Helix‐out conformation. In this instance, the C‐helix moved significantly to create a large hydrophobic pocket rarely seen in kinase protein crystal structures.

Progress in the Development of Inhaled, Long-Acting β2-Adrenoceptor Agonists

Publisher Summary Long acting β 2 -adrenoceptor agonists are a highly precedented drug class used for the treatment of asthma and chronic obstructive pulmonary disease (COPD). There are currently two marketed long acting β 2 -adrenoceptor agonists—salmeterol 1 and formoterol 2—neither of which provides a once daily dosing regimen. This chapter discusses various β 2 -adrenoceptor agonist head groups—including 8-hydroxycarbostyril, formamides, and saligenins—employed by researchers and discusses the potential development of dual pharmacology agents. The 8-hydroxycarbostyril moiety is known to have a high affinity for the β 2 -adrenoceptor and has been postulated to give potential slow offset properties to ligands to drive the duration of action. A recently published patent suggests that the maleate salt of indacaterol is highly crystalline, stable, and may be the preferred form of this compound for development and clinical use. The saligenin head group has been used with success to prepare long acting β 2 -adrenoceptor agonists with salmeterol playing a prominent role as a benchmark compound. In this connection, the combination agent Advair™ (salmeterol and fluticasone) is currently in third place globally in terms of sales, thereby demonstrating the success of this approach. The dual pharmacology approach presents a number of potential advantages, including the ease of formulation, simpler pharmacokinetics, and the option of combining the dual agent with a third pharmacology in the inhaler. The most notable effort to combine a second pharmacology with β 2 -adrenoceptor agonism is the development of sibenadet (AR-C68397AA).

Designing rapid onset selective serotonin re-uptake inhibitors. 2: structure-activity relationships of substituted (aryl)benzylamines.

A series of substituted benzylamines 2-48 were prepared as part of a strategy to identify structurally differentiated and synthetically more accessible selective serotonin reuptake inhibitors, relative to clinical candidate 1. In particular, 44 and 48; demonstrated low nanomolar potency and good selectivity, in a structurally simplified template and, in vivo, very low Vdu, significantly lower than l, and a more rapid T(max), consistent with our clinical objectives.

Design and synthesis of long acting inhaled corticosteroids for the treatment of asthma

In this Letter we present data for a novel series of ICS for the treatment of asthma. Inhalation by design principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimise systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance as well as glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimise drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity and solubility were considered to ensure compatibility with a dry powder inhaler. This work culminated in the identification of the clinical candidate 15, which demonstrates preclinically the desired efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of asthma.

Designing rapid onset selective serotonin re-uptake inhibitors. Part 3: Site-directed metabolism as a strategy to avoid active circulating metabolites: Structure–activity relationships of (thioalkyl)phenoxy benzylamines

A series of thio-alkyl containing diphenylethers were designed and evaluated, as a strategy to competitively direct metabolism away from unwanted amine N-demethylation and deliver a pharmacologically inactive S-oxide metabolite. Overall, sulfonamide 20 was found to possess the best balance of target pharmacology, pharmacokinetics and metabolism profile.

Molecular hybridization yields triazole bronchodilators for the treatment of COPD

A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a β2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of inhalation by design furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.

Small-molecule anti-inflammatory drug compositions for the treatment of asthma: a patent review (2013 – 2014)

Introduction: Asthma is a chronic condition affecting 235 million people worldwide, with prevalence continuing to increase. A significant number of patients have poorly controlled asthma but despite this, a new mechanistic class of small-molecule asthma therapy has not emerged over the past 15 years. Areas covered: In this article, the authors review the published patent literature from 2013 to 2014 that describes the discovery of novel small-molecule anti-inflammatory agents for the treatment of asthma. This patent analysis was performed using multiple search engines including SciFinder and Free Patents Online. Expert opinion: This review highlights that significant research is still directed towards the development of novel anti-inflammatory agents for the treatment of asthma. Current standard-of-care therapies are given topically to the lung via an inhaled dose, which the authors believe can offer significant advantages in terms of efficacy and therapeutic index, compared with an oral dose. Several of the patents reviewed disclose preferred compounds and data that suggest an inhaled approach is being specifically pursued. The patents reviewed target a wide range of inflammatory pathways, although none have yet delivered an approved novel medicine for asthma; this gives an indication of both the opportunity and challenge involved in such an endeavor.