Synthesis and Structure–Activity Relationship of Tetra-Substituted Cyclohexyl Diol Inhibitors of Proviral Insertion of Moloney Virus (PIM) Kinases

Abstract

Overexpression of PIM 1, 2, and 3 kinases is frequently observed in many malignancies. Previously, we discovered a potent and selective pan-PIM kinase inhibitor, compound 2, currently in phase I clinical trials. In this work, we were interested in replacing the amino group on the cyclohexane ring in compound 2 with a hydroxyl group. Structure-based drug design led to cellularly potent but metabolically unstable tetra-substituted cyclohexyl diols. Efforts on the reduction of Log D by introducing polar heterocycles improved metabolic stability. Incorporating fluorine to the tetra-substituted cyclohexyl diol moiety further reduced Log D, resulting in compound 14, a cellularly potent tetra-substituted cyclohexyl diol inhibitor with moderate metabolic stability and good permeability. We also describe the development of efficient and scalable synthetic routes toward synthetically challenging tetrasubstituted cyclohexyl diol compounds. In particular, intermediate 36 was identified as a versatile intermediate, enabling a large-scale synthesis of highly substituted cyclohexane derivatives.

Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles

“…It is noteworthy that 102 did not exhibit strong inhibitory activity against CYP450 enzymes and hERG potassium channels, indicating favorable characteristics in terms of metabolic stability, drug−drug interactions, and cardiac safety (Figure 10J). 127 Currently, most of the research focuses on the interaction with PIM-1, but considering the benefits of multitarget inhibition, it is desirable for future inhibitors to also consider the inhibitory effects on PIM-2 and PIM-3. Moreover, low bioavailability remains a key concern in the development of pan-PIM small molecule inhibitors, as seen in 92, which exhibits strong enzyme inhibitory activity and good cytotoxicity against tumor cells.…”

“…However, this fluorine addition also resulted in reduced solubility. It is noteworthy that 102 did not exhibit strong inhibitory activity against CYP450 enzymes and hERG potassium channels, indicating favorable characteristics in terms of metabolic stability, drug–drug interactions, and cardiac safety (Figure J) …”

Simple inorganic base promoted polycyclic construction using mucohalic acid as a C3 synthon: synthesis and AIE probe application of benzo[4,5]imidazo[1,2-a]pyridines

“…There are only a few studies on the use of mucohalic acids as C 3 synthons for the synthesis of fused heterocyclic compounds. 27…”

Understanding and Controlling the Mizoroki–Heck Reaction of Cyclic Enones

“…For example, 3-aryl cyclic enones can be accessed by oxidative coupling of the unsubstituted enone with boronic acids, cross-coupling of 3-(pseudo)­haloenones, oxidative rearrangement of allylic alcohols formed from 1,2-addition, and addition/elimination sequences with 3-alkoxy enones (Scheme A). Our interest in these molecules stems from an abundance of chiral 3-arylated cyclic alcohols that are present in important therapeutics, which might be accessible from arylated enones via stereocontrolled reduction using appropriate enzymes . To our surprise, the Mizoroki–Heck reaction, which is arguably the most direct and powerful method to arylate simple alkenes, is not well represented among common strategies to access 3-aryl cyclic enones despite acyclic-conjugated alkenes being prototypical substrates.…”