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.

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