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    • Optimization of the B ring specifically targeted

    2023-12-19

    Optimization of the B-ring specifically targeted preventing the oxidation of the ring system (). As described above, the 4-position of the phenyl ring provides the appropriate vector towards bulk solvent. - and -linked substitutions at the 4-position of the B-ring from the 4-fluoro-nitrophenyl intermediate were accessible based on a Sn reaction with an amine (–) or alcohol () (). The 4-amino series was also shown to improve as seen with CGP 54626 hydrochloride mg (,) and others in the series (data not shown). The 4-oxo analog () also showed significant improvement in the enzymatic and cell potency, however, improvements in the metabolic stability in both rat and human were not as substantial as in the 4-amino series. Based on the improved cell potency and microsomal stability, compound () was further profiled (). CYP profiling for () showed no CYP inhibition across the CYP isoforms tested. Compound () was shown to have low plasma protein binding (PPB%(h/r)=79/90%). Compound () showed good permeability in PAMPA assay (184nm/s) and demonstrated good oral exposure in rat PK studies (F=38%, CL=53 (mg/kg/min)). Compound () exhibited high clearance close to hepatic blood flow, which is likely due to non-oxidative clearance mechanism since the rat microsomes (CL=35mg/kg/min) did not indicate such high clearance. Compound () also shows improved hERG inhibition (19%@10μM) compared to the initial lead () (94%@10μM). Finally, compound () was tested against a 56 kinase panel which showed that it was a highly selective Axl inhibitor (data not shown). A cocrystal structure was obtained for compound () () and showed the expected interactions as well as the morpholino group pointed towards the solvent-exposed region. In conclusion, we have developed compound () as an Axl selective inhibitor which shows single digit nanomolar enzymatic potency. We were able to improve the cellular potency in this series with compound () compared to compound (). Microsomal stability was also improved in rat and human microsomes, and although compound () showed higher than predicted metabolism, this compound showed an improved absorption profile compared to compound (). In spite of the fact that compound () has an aniline structural alert, it will serve as a useful, selective tool compound. Taken together, this compound represents a useful molecule for further target validation studies to support the role of Axl in cancer.