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.

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Female sexual arousal disorder (FSAD) is a highly prevalent sexual disorder affecting up to 40% of women. We describe herein our efforts to identify a selective neutral endopeptidase (NEP) inhibitor as a potential treatment for FSAD. The rationale for this approach, together with a description of the medicinal chemistry strategy, lead compounds, and SAR investigations are detailed. In particular, the strategy of starting with the clinically precedented selective NEP inhibitor, Candoxatrilat, and targeting low molecular weight and relatively polar mono-carboxylic acids is described. This led ultimately to the prototype development candidate R-13, for which detailed pharmacology and pharmacokinetic parameters are presented.(1)

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Pyrazine derivatives Pyrazine derivatives R 0550Design, Synthesis and Biological Activity of β-Carboline-Based Type-5 Phosphodiesterase Inhibitors. -The N-methyl group in tadalafil is targeted for structural modification to investigate the selectivity profile, especially phosphodiesterase 5 selectivity over phosphodiesterase 11. The initial strategy is based on introducing a basic nitrogen into the molecule to improve aqueous solubility and to assess its impact on PDE5 potency and selectivity. Key intermediate (V) reacts with a range of primary diamines to yield compounds (VII) including pyrrolidine (VIIc) which exhibits a remarkable increase in enzyme inhibition potency. This compound is selected for optimization of the N-substituent and converted into a range of N-alkyl derivatives such as (X). This series has excellent levels of PDE5 potency and selectivity over PDE6. Unfortunately, this series shows low levels of selectivity over PDE 11. -(MAW*, G. N.; ALLERTON, C. M. N.; GBEKOR, E.; MILLION, W. A.; Bioorg. Med. Chem. Lett.