Synthesis and Evaluation of Novel Tetrahydronaphthyridine CXCR4 Antagonists with Improved Drug-like Profiles

Our
first-generation CXCR4 antagonist TIQ15 was rationally modified
to improve drug-like properties. Introducing a nitrogen atom into
the aromatic portion of the tetrahydroisoquinoline ring led to several
heterocyclic variants including the 5,6,7,8-tetrahydro-1,6-naphthyridine
series, greatly reducing the inhibition of the CYP 2D6 enzyme. Compound 12a demonstrated the best overall properties after profiling
a series of isomeric tetrahydronaphthyridine analogues in a battery
of biochemical assays including CXCR4 antagonism, CYP 2D6 inhibition,
metabolic stability, and permeability. The butyl amine side chain
of 12a was substituted with various lipophilic groups
to improve the permeability. These efforts culminated in the discovery
of compound 30 as a potent CXCR4 antagonist (IC50 = 24 nM) with diminished CYP 2D6 activity, improved PAMPA permeability
(309 nm/s), potent inhibition of human immunodeficiency virus entry
(IC50 = 7 nM), a cleaner off-target in vitro safety profile,
lower human ether a-go-go-related gene channel activity, and higher
oral bioavailability in mice (% FPO =
27) compared to AMD11070 and TIQ15.