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.

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.

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 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.

Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion.

RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC50 of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo.

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.