Synthesis and Profiling of a Diverse Collection of Azetidine-Based Scaffolds for the Development of CNS-Focused Lead-like Libraries

Abstract

The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of 1976-membered library of a spirocyclic azetidines is also described.

Single Diastereomer of a Macrolactam Core Binds Specifically to Myeloid Cell Leukemia 1 (MCL1)

“…30,31 The 19 F NMR resonance of the CF 3 group, in particular, was significantly shifted in the presence of MCL1 (Δv = 5.4 Hz at 60 μM ligand, 10 μM protein), with significant line-broadening as expected for a slower-tumbling protein− ligand complex. Using 19 F NMR detection, we measured an intrinsic K D = 6 μM for macrolactam 7 binding to MCL1, which is in good agreement with affinity measured by ITC.…”

“…Thus, this direct binding discovery effort has identified a novel macrolactam, which selectively binds in the hydrophobic BH3 binding groove of MCL1. Having thus validated the binding of macrolactam 7 by several additional biophysical methods (DSC, ITC, 19 F NMR, and FP), we were encouraged to explore the structure-binding relationships of this novel scaffold. Several analogues were synthesized in straightforward fashion to probe both the urea and sulfonamide portions of 7 (Tables 1 and 2).…”

Assessing molecular scaffolds for CNS drug discovery

“…The identification of novel and diverse scaffolds that, on decoration, would yield lead-like compounds for CNS drug discovery is a significant challenge [22]. Whilst the scoring protocols described earlier have been constructed based on the properties of drugs and candidate drugs, no method currently exists that has been specifically designed for the purpose of assessing CNS lead-likeness.…”

Transition metal-free one-pot synthesis of nitrogen-containing heterocycles

“…Azetidine and its derivatives are of high interest due to their versatility in medicinal chemistry as well as in synthetic chemistry [29,30]. Antibiotics containing azetidine have been known for decades for their unsurpassed clinical efficacy and safety.…”