Lowering Lipophilicity by Adding Carbon: AzaSpiroHeptanes, a logD Lowering Twist.

ABSTRACT: We have conducted an analysis of azaspiro[3.3]heptanes used as replacements for morpholines, piperidines, and piperazines in a medicinal chemistry context. In most cases, introducing a spirocyclic center lowered the measured logD _7.4 of the corresponding molecules by as much as -1.0 relative to the more usual heterocycle. This may seem counterintuitive, as the net change in the molecule is the addition of a single carbon atom, but it may be rationalized in terms of increased basicity. An exception to this was found with N-linked 2-azaspiro[3.3]heptane, where logD _7.4 increased by as much as +0.5, consistent with the addition of carbon. During our investigation, we also concluded that azaspiro[3.3]heptanes are most likely not suitable bioisosteres

SUBMITTER: Degorce SL 

PROVIDER: S-EPMC6693472 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature