Design, Synthesis, and Biological Evaluation of 4‑Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase

We pursued a structure-guided approach
toward the development of
improved dihydroorotate dehydrogenase (DHODH) inhibitors with the
goal of forming new interactions between DHODH and the brequinar class
of inhibitors. Two potential residues, T63 and Y356, suitable for
novel H-bonding interactions, were identified in the brequinar-binding
pocket. Analogues were designed to maintain the essential pharmacophore
and form new electrostatic interactions through strategically positioned
H-bond accepting groups. This effort led to the discovery of potent
quinoline-based analogues 41 (DHODH IC50 =
9.71 ± 1.4 nM) and 43 (DHODH IC50 = 26.2
± 1.8 nM). A cocrystal structure between 43 and
DHODH depicts a novel water mediated H-bond interaction with T63.
Additional optimization led to the 1,7-naphthyridine 46 (DHODH IC50 = 28.3 ± 3.3 nM) that forms a novel
H-bond with Y356. Importantly, compound 41 possesses
significant oral bioavailability (F = 56%) and an
elimination t1/2 = 2.78 h (PO dosing).
In conclusion, the data supports further preclinical studies of our
lead compounds toward selection of a candidate for early-stage clinical
development.