Robert M. Owen

Ion Channels as Therapeutic Targets: A Drug Discovery Perspective

Ion channels are membrane proteins expressed in almost all living cells. The sequencing of the human genome has identified more than 400 putative ion channels, but only a fraction of these have been cloned and functionally tested. The widespread tissue distribution of ion channels, coupled with the plethora of physiological consequences of their opening and closing, makes ion-channel-targeted drug discovery highly compelling. However, despite some important drugs in clinical use today, as a class, ion channels remain underexploited in drug discovery and many existing drugs are poorly selective with significant toxicities or suboptimal efficacy. This Perspective seeks to review the ion channel family, its structural and functional features, and the diseases that are known to be modulated by members of the family. In particular, we will explore the structure and properties of known ligands and consider the future prospects for drug discovery in this challenging but high potential area.

5-(2-Pyrimidinyl)-imidazo[1,2-a]pyridines are antibacterial agents targeting the ATPase domains of DNA gyrase and topoisomerase IV

Dual inhibitors of bacterial gyrB and parE based on a 5-(2-pyrimidinyl)-imidazo[1,2-a]pyridine template exhibited MICs (microg/mL) of 0.06-64 (Sau), 0.25-64 (MRSA), 0.06-64 (Spy), 0.06-64 (Spn), and 0.03-64 (FQR Spn). Selected examples were efficacious in mouse sepsis and lung infection models at <50mg/kg (PO dosing).

Voltage gated sodium channels as drug discovery targets.

Voltage-gated sodium (NaV) channels are a family of transmembrane ion channel proteins. They function by forming a gated, water-filled pore to help establish and control cell membrane potential via control of the flow of ions between the intracellular and the extracellular environments. Blockade of NaVs has been successfully accomplished in the clinic to enable control of pathological firing patterns that occur in a diverse range of conditions such as chronic pain, epilepsy, and cardiac arrhythmias. First generation sodium channel modulator drugs, despite low inherent subtype selectivity, preferentially act on over-excited cells which reduces undesirable side effects in the clinic. However, the limited therapeutic indices observed with the first generation demanded a new generation of sodium channel inhibitors. The structure, function and the state of the art in sodium channel modulator drug discovery are discussed in this chapter.

Discovery of a Selective TRPM8 Antagonist with Clinical Efficacy in Cold-Related Pain

The transient receptor potential (TRP) family of ion channels comprises nonselective cation channels that respond to a wide range of chemical and thermal stimuli. TRPM8, a member of the melastatin subfamily, is activated by cold temperatures (<28 °C), and antagonists of this channel have the potential to treat cold induced allodynia and hyperalgesia. However, TRPM8 has also been implicated in mammalian thermoregulation and antagonists have the potential to induce hypothermia in patients. We report herein the identification and optimization of a series of TRPM8 antagonists that ultimately led to the discovery of PF-05105679. The clinical finding with this compound will be discussed, including both efficacy and its ability to affect thermoregulation processes in humans.

Targeting the cAMP and Transforming Growth Factor-β Pathway Increases Proliferation to Promote Re-Epithelialization of Human Stem Cell-Derived Retinal Pigment Epithelium

Retinal pigment epithelium (RPE) cell integrity is critical to the maintenance of retinal function. Many retinopathies such as age‐related macular degeneration (AMD) are caused by the degeneration or malfunction of the RPE cell layer. Replacement of diseased RPE with healthy, stem cell‐derived RPE is a potential therapeutic strategy for treating AMD. Human embryonic stem cells (hESCs) differentiated into RPE progeny have the potential to provide an unlimited supply of cells for transplantation, but challenges around scalability and efficiency of the differentiation process still remain. Using hESC‐derived RPE as a cellular model, we sought to understand mechanisms that could be modulated to increase RPE yield after differentiation. We show that RPE epithelialization is a density‐dependent process, and cells seeded at low density fail to epithelialize. We demonstrate that activation of the cAMP pathway increases proliferation of dissociated RPE in culture, in part through inhibition of transforming growth factor‐β (TGF‐β) signaling. This results in enhanced uptake of epithelial identity, even in cultures seeded at low density. In line with these findings, targeted manipulation of the TGF‐β pathway with small molecules produces an increase in efficiency of RPE re‐epithelialization. Taken together, these data highlight mechanisms that promote epithelial fate acquisition in stem cell‐derived RPE. Modulation of these pathways has the potential to favorably impact scalability and clinical translation of hESC‐derived RPE as a cell therapy.

The discovery and evaluation of diaryl ether heterocyclic sulfonamides as URAT1 inhibitors for the treatment of gout

Elevated serum uric acid levels can lead to gout which remains an area of unmet medical need. Following an unexpected clinical uricosuric effect observed with a sulfonamide compound, PF-05089771 (9), subsequently attributed to weak URAT1 inhibition, the optimization of a series of acidic sulfonamides as selective URAT1 inhibitors was undertaken. Compounds 10f and 10i were identified as suitable leads for more extensive profiling after exhibiting high URAT1 inhibitory potency and subsequently demonstrated promising preclinical ADME and safety profiles.

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

Benzodiazepines, non‐selective positive allosteric modulators (PAMs) of GABAA 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.

The design, synthesis and evaluation of low molecular weight acidic sulfonamides as URAT1 inhibitors for the treatment of gout

A novel series of low molecular weight and synthetically facile acidic sulfonamides that are potent and selective URAT1 inhibitors is described. Compounds 46 and 47 were identified as promising leads from in vitro pharmacology and ADME profiling and advanced to broader in vitro and in vivo PK and toxicology studies.