Michael John Palmer

A dynamic model of HIV integrase inhibition and drug resistance.

Human immunodeficiency virus type 1 (HIV-1) integrase is one of three virally encoded enzymes essential for replication and, therefore, a rational choice as a drug target for the treatment of HIV-1-infected individuals. In 2007, raltegravir became the first integrase inhibitor approved for use in the treatment of HIV-infected patients, more than a decade since the approval of the first protease inhibitor (saquinavir, Hoffman La-Roche, 1995) and two decades since the approval of the first reverse transcriptase inhibitor (retrovir, GlaxoSmithKline, 1987). The slow progress toward a clinically effective HIV-1 integrase inhibitor can at least in part be attributed to a poor structural understanding of this key viral protein. Here we describe the development of a restrained molecular dynamics protocol that produces a more accurate model of the active site of this drug target. This model provides an advance on previously described models as it ensures that the catalytic DDE motif makes correct, monodentate interactions with the two active-site magnesium ions. Dynamic restraints applied to this coordination state create models with the correct solvation sphere for the metal ion complex and highlight the coordination sites available for metal-binding ligands. Application of appropriate dynamic flexibility to the core domain allowed the inclusion of multiple conformational states in subsequent docking studies. These models have allowed us to (1) explore the effects of key drug resistance mutations on the dynamic flexibility and conformational preferences of HIV integrase and to (2) study raltegravir binding in the context of these dynamic models of both wild type and the G140S/Q148H drug-resistant enzyme.

Design of second generation phosphodiesterase 5 inhibitors.

The clinical significance of phosphodiesterase 5 (PDE5) inhibition is increasingly understood following the pioneering work with sildenafil, and the continuing development programmes for both sildenafil and other marketed inhibitors. Since the initial launch of sildenafil for male erectile dysfunction (MED), approval has now been granted for treatment of pulmonary hypertension, whilst ongoing studies have indicated the potential of PDE5 inhibition for the treatment of a range of additional indications including cardioprotection, memory retention and diabetes. Many of these additional indications are best suited to chronic oral dosing and emphasise the need for highly selective inhibitors with extended duration of action. This article will focus on a research programme aimed at the discovery of improved second-generation PDE5 inhibitors. Essential features of these new PDE5 inhibitors would be enhanced selectivity across the whole PDE family and pharmacokinetics compatible with once daily dosing. Key elements used in this programme are high throughput screening (HTS), exploitation of co-crystal structural information for bound inhibitor in the PDE5 active site, and employment of parallel chemistry to speed progress. Under the guidance of co-crystal structural information, a non-selective HTS hit with poor physicochemistry was initially modified using parallel chemistry to give a lead compound (3) that established a new PDE5 inhibitor series. Notably, (3) displayed physicochemistry compatible with a long plasma half-life, and wide chemical scope. Subsequent optimisation of (3) using crystal structure information to guide design, led rapidly to highly potent and selective PDE5 inhibitors (47, 50). Continued focus on physical properties through ligand efficiency evaluation and lipophilicity (cLogP), maintained the inherently desirable physicochemistry of the initial lead.

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 potent, selective, and orally bioavailable PDE9 inhibitors as potential hypoglycemic agents

Starting from a non-selective pyrazolo-pyrimidone lead, the sequential use of parallel medicinal chemistry and directed synthesis led to the discovery of potent, highly selective, and orally bioavailable PDE9 inhibitors. The availability of these tools allowed for a thorough evaluation of the therapeutic potential of PDE9 inhibition.

Novel phosphodiesterase type 5 modulators: a patent survey (2008 – 2010)

Introduction: The inhibition of cyclic nucleotide PDE5 has been clinically validated as an effective treatment for erectile dysfunction and pulmonary arterial hypertension. There are three PDE5 inhibitors (sildenafil, vardenafil and tadalafil) approved worldwide and a further two agents (udenafil and mirodenafil) approved only in Korea. These first generation agents are perceived to have flaws in selectivity over other PDEs: slow onset, duration of action or CNS penetration, which has driven further research to identify optimal PDE5 inhibitors for the current pathologies. Several clinical trials have been reported to investigate the potential for PDE5 inhibitors to treat additional indications, which might require agents with different biological and/or pharmacokinetic profiles. Areas covered: This review provides a summary of developments in the patent and open literature over the period 2008 – 2010. Expert opinion: Avanafil, the first of a new generation of PDE5 inhibitors, has shown encouraging efficacy in clinical trials, and is likely to result in a new drug application filing during 2011, followed by a possible launch in 2012. Judging by the wealth of different structural series being claimed in patents, it seems that the selectivity and pharmacokinetic issues facing the first generation can be addressed through novel chemical matter.

Identification, synthesis and SAR of amino substituted pyrido(3,2b)pyrazinones as potent and selective PDE5 inhibitors

A new class of potent and selective PDE5 inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure-activity relationships are also presented.

Endothelin Receptor Antagonists : Status and Learning 20 Years On

Publisher Summary This chapter presents the current biology and clinical status of endothelin receptor antagonists and reviews the array of different antagonist series. The field of endothelin receptor antagonists represents one of the most researched areas in medicinal chemistry. The vast array of important biological effects that are influenced by the endothelin family of peptides and the plethora of different chemical classes that have subsequently arisen provide a great opportunity to study the targeting of two difficult peptidic types—both belong to class 1 of the G-protein-coupled receptor (GPCR). The endothelin, ET A and ET B , receptors fall into the peptidic GPCR family, and the analyses support the hypothesis that this receptor family generally represents a challenging drug target. Structural biology application to antagonist design strategy, in terms of ET-1 mimicking, or pharmacophore models are highlighted in the various chemical classes of antagonist that have emerged. Te challenge of achieving a suitable therapeutic index may prove a key factor in defining the potential of endothelin receptor antagonists.

1-(2-(2,2,2-trifluoroethoxy)ethyl-1H-pyrazolo[4,3-d]pyrimidines as potent phosphodiesterase 5 (PDE5) inhibitors.

1H-Pyrazolo[4,3-d]pyrimidines were previously disclosed as a potent second generation class of phosphodiesterase 5 (PDE5) inhibitors. This work explores the advancement of more selective and potent PDE5 inhibitors resulting from the substitution of 2-(2,2,2-trifluoroethoxy)ethyl at the 1 position in the so-called alkoxy pocket.

A convenient synthesis of 2,4-diaminoquinoline derivatives

Abstract Base or Lewis acid induced cyclisation of the o-amidinobenzonitriles (III) provides 2,4-diaminoquinoline derivatives (IV) in high yield.

Leads for the treatment of pulmonary hypertension

Background: Knowledge of the causative reasons for pulmonary arterial hypertension, a major category of pulmonary hypertension, has expanded dramatically over the past 10 years. This has led to heightened research across a range of potential new mechanistic approaches and resulted in the identification of further treatment options, together with several promising leads and prototypes. Objective: This review aims to summarise and assess the most relevant research fields, covering key publications and recent patent literature. Methods: Searching revealed in excess of 700 patents claiming uses that relate to pulmonary hypertension. These patents were filtered into key therapeutic approaches based on pharmacological reviews of the pulmonary arterial hypertension field. Results/conclusions: Endothelin antagonists and phosphodiesterase 5 inhibitors have emerged as recently approved treatment options and are proving extremely beneficial. Further new mechanistic approaches have yielded promising leads, some of which have the potential to be disease modifying; notably, tyrosine kinase inhibitors, soluble guanylate cyclase agonists, Rho-kinase inhibitors, vasoactive intestinal peptide analogues and 5-HT antagonists.