Rigidification of Propoxy Linker

We were interested in exploring the replacement of the propoxy linker with a cyclobutoxy spacer, the latter presenting the advantage of being the most compact cyclic constraint still incorporating the three-carbon spacer. This work was done in collaboration with Amsterdam University [51]. 

CYP2D6/3A4 33% / 6% inh 10uM Cl (rat microsomes) 20 itymln/mg protein Papps (Caco-2) 160 nm/sec 

In order to further expand the chemical diversity and identify an additional chemical series before transitioning, we were appealed to try using a five-mem-bered lactam (pyrrolidinone) as a suitable surrogate for the oxazoline or oxazole group. This suggestion was further supported by molecular modeling studies that showed a good overlap between lactam and oxazole derivatives in the H3 

Given our past experience in the field of pyrrolidinone chemistry and the observed benefits this particular group may bring in terms of physicochemical and pharmacokinetic properties [54], we decided to deeply explore the chemical space around lactams. 

NR R R Hb pK hERG iQo logD PKa values Clin, hum./ rat Papps  

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