Graham Lunn

Investigation of the effect of molecular properties on the binding kinetics of a ligand to its biological target

A database of binding kinetic data across multiple targets has been created. Analysis of this database provides insights into trends for the effects of physicochemical properties (molecular weight, clogP, rotatable bond count) on the dissociation kinetics of ligands from their biological targets.

Full efficacy with no CNS side-effects: unachievable panacea or reality? DMPK considerations in design of drugs with limited brain penetration

Optimising drug properties can be an important strategy to limit penetration into the CNS and offers advantages in reducing the risk of undesirable neurological effects When considering the design of these drugs it is important to consider the relative influx and efflux rates at the relevant biological membranes The highest degree of restriction at the brain is probably achievable by utilising active transport to exclude compounds from the brain Affinity for the efflux transporters Pgp and BCRP has been achieved in two in-house chemistry programmes by increasing polar surface area, which resulted in highly orally bioavailable low CNS penetrant compounds in preclinical species

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.

Discovery and synthesis of a new class of opioid ligand having a 3-azabicyclo[3.1.0]hexane core. An example of a 'magic methyl' giving a 35-fold improvement in binding.

In looking for a novel achiral μ opioid receptor antagonist for the treatment of pruritus, we designed and synthesised azabicyclo[3.1.0]hexane compounds as a new class of opioid ligand. During optimisation, an addition of a single methyl resulted in a 35-fold improvement in binding. An early example from the series had excellent μ opioid receptor antagonist antagonist activity and was very effective in an in vivo pruritus study.

SAR and biological evaluation of 3-azabicyclo[3.1.0]hexane derivatives as μ opioid ligands.

3-Azabicyclo[3.1.0]hexane compounds were designed as novel achiral μ opioid receptor ligands for the treatment of pruritus in dogs. In this paper, we describe the SAR of this class of opioid ligand, highlighting changes to the lead structure which led to compounds having picomolar binding affinity, selective for the μ receptor over δ and κ subtypes. Some subtleties of functional activity will also be described.

The discovery and profile of PF-0868087, a CNS-sparing histamine H3 receptor antagonist for the treatment of allergic rhinitis

We wished to identify a CNS-sparing histamine H3 receptor antagonist for the treatment of allergic rhinitis. We aimed for compounds with low permeability, high solubility, that were substrates for the BBB efflux transporters MDR-1 and BCRP. The key lead PF-0868087 demonstrated over a 10-fold CNS-sparing profile in 2 preclinical species.

Optimized glucuronidation of dual pharmacology β-2 agonists/M3 antagonists for the treatment of COPD

‘Inhalation by design’ concepts were developed to create novel dual pharmacology β-2 agonists-M3 antagonists, for the treatment of chronic obstructive pulmonary disorder. A key feature of this work is the combination of balanced potency and pharmacological duration with optimised glucuronidation through the incorporation of metabolically vulnerable phenols.

Use of libraries to access new chemical space: Applications to CRTH2

The generation of novel CRTH2 ligands in heavily congested chemical space, by de novo design of libraries is disclosed. Novel (1719) compounds across seven libraries were synthesised. More than 100 of these compounds showed binding potency <3 μM against CRTH2, with the most potent being 247 nM. These libraries produced novel series and demonstrated that this approach is a viable one.