Graham Nigel Maw

Design, synthesis and biological activity of β-carboline-based type-5 phosphodiesterase inhibitors

The SAR of a series of beta-carboline derived type 5 phosphodiesterase inhibitors has been explored and we have discovered compounds with excellent levels of PDE5 potency and selectivity over PDE6. However, the series exhibits low levels of selectivity over PDE11, a phosphodiesterase with unknown function.

Chemoselectivity in the chromium(II)-mediated synthesis of E-alkenylstannanes from aldehydes and Bu3SnCHBr2

Abstract The synthesis of functionalised E-alkenylstannanes from aldehydes and a mixture of Bu3SnCHBr2, LiI and CrCl2 is described.

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.

Scope of the chromium(II)-mediated synthesis of E-alkenylstannanes from aldehydes and Bu3SnCHBr2

Abstract The synthesis of E-alkenylstannanes from aldehydes and a mixture of Bu3SnCHBr2, LiI and CrCl2 is described. A mechanism is proposed to account for the alkene geometry in chromium(II)-mediated alkene synthesis which involves stereoselective addition by a gem-dichromium reagent to an aldehyde followed by a stereospecific elimination step.

SAR of a series of inhaled A(2A) agonists and comparison of inhaled pharmacokinetics in a preclinical model with clinical pharmacokinetic data.

COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists is described leading through to human pharmacokinetic data for a clinical candidate.

Inhaled adenosine A2A receptor agonists for the treatment of chronic obstructive pulmonary disease

COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was followed and pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists described. A sevenfold improvement in potency and 150-fold reduction in side-effect liability over the lead compound CGS-21680, were obtained.

Chapter 8. Pharmacological Therapy for the Treatment of Erectile Dysfunction

Publisher Summary This chapter elaborates pharmacological therapy for the treatment of erectile dysfunction (ED), which is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance. Erection is triggered and maintained via central nervous control through two different nerve pathways. Reflex erections are under spinal control and psychogenic erections under direct central control. In healthy males, these two mechanisms are believed to work synergistically in the control of erections. Therefore any reduction of neuronal function by peripheral neuropathy associated with diabetes, for example, can also lead to ED. In addition, spinal cord injury can also contribute to the presence of ED through loss of central control, although the reflexogenic pathway still operates. Basics of physiology of the penis and mechanism of erection are elaborated in the chapter. Drugs approved for the treatment of ED are described and central control of penile erection is explained. Concepts related to investigational drugs for ED are discussed. Novel PDE5 inhibitors are elaborated and also non-selective PDE5 inhibitors are analyzed.

Discovery and Optimization of Selective Nav1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain

Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described the optimization of Nav1.8 modulator series to deliver subtype selective, state, and use-dependent chemical matter that is efficacious in preclinical models of neuropathic and inflammatory pain.

An unusual Michael addition–dealkylation or elimination via the reaction of tertiary or secondary amines with a (Z)-iodoacrylate

Abstract A series of ( E )-ammonium or amino acrylates have been prepared via the Michael addition of methyl ( Z )-iodoacrylate and several secondary and tertiary alkylamines. Tertiary amines undergo concomitant addition–dealkylation, almost quantitatively producing ( E )-dialkylamino acrylates.

The discovery of UK-369003, a novel PDE5 inhibitor with the potential for oral bioavailability and dose-proportional pharmacokinetics

This paper describes our recent efforts to design and synthesise potent and selective PDE5 inhibitors and the use of in vitro predictors of clearance, absorption and permeability to maximise the potential for dose-proportional pharmacokinetics and good oral bioavailability in man. Optimisation of the preclinical profile resulted in the identification of UK-369003 (19a) and its nomination as a clinical candidate. The clinical pharmacokinetic and safety profile has enabled us to progress the compound to test its efficacy in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and a paper describing its efficacy has recently been published.