In this interesting J.Med.Chem. article workers from Roche describe the optimisation of a series of benzoylpiperazines as Gly-T1 inhibitors for the treatment of schizophrenia culminating in the discovery of RG1678, the first potent and selective Gly-T1 inhibitor to demonstrate efficacy in a phase II clinical trial in schizophrenic patients. The authors outline how RG1678 evolved from an early lead compound (9) which had an attractive in vitro and in vivo efficacy profile yet suffered from a pronounced hERG activity which prevented it’s further development.
The cyclopropyl methoxy substituent in the 2-position of the benzoyl motif fits into a size-limited, lipophilic pocket in the Gly-T1 receptor. Changing this group to smaller or more highly fluorinated alkyl groups was beneficial with respect to hERG inhibition and trifluoroisopropyloxy emerged as a favoured group. Replacing the cyano group in 9 with a CF3 lowered the PSA and improved the overall level of brain penetration and indeed, in this series of compounds, CNS penetration was well predicted using PSA and clogP as descriptors. Interestingly the CF3 substituent also produced a somewhat counter intuitive drop in hERG affinity (usually increasing lipophilicity has the opposite effect) which the Roche scientists attribute to a specific H-bonding interaction between the cyano group and an amino acid residue in the hERG channel. Finally, increasing polarity by replacing the western aromatic nucleus of 9 with heteroaromatic systems was explored in an effort to reduce hERG activity yet further. Whilst most of these replacements (e.g. pyrazine, pyrimidine, and pyridazine) led to decreased Gly-T1 activity, the pyridine derivatives were well tolerated and led for the first time to compounds with 500-fold selectivity over hERG. RG1678 is not particulary soluble in water (1ug/mL from crystals at pH 6.5) but has excellent permeability and improved solubility in FaSSIF (20ug/mL) and FeSSIF (60ug/mL). RG1678 has an excellent preclinical profile and the complete biological profile is promised in forthcoming publications. The phase II efficacy data (against negative symptoms) sounds very promising and it will be interesting to follow the development of this compound.