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 <b>41</b> (DHODH IC₅₀ = 9.71 ± 1.4 nM) and <b>43</b> (DHODH IC₅₀ = 26.2 ± 1.8 nM). A cocrystal structure between <b>43</b> and DHODH depicts a novel water mediated H-bond interaction with T63. Additional optimization led to the 1,7-naphthyridine <b>46</b> (DHODH IC₅₀ = 28.3 ± 3.3 nM) that forms a novel H-bond with Y356. Importantly, compound <b>41</b> possesses significant oral bioavailability (<i>F</i> = 56%) and an elimination <i>t</i>_1/2 = 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

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 <b>41</b> (DHODH IC₅₀ = 9.71 ± 1.4 nM) and <b>43</b> (DHODH IC₅₀ = 26.2 ± 1.8 nM). A cocrystal structure between <b>43</b> and DHODH depicts a novel water mediated H-bond interaction with T63. Additional optimization led to the 1,7-naphthyridine <b>46</b> (DHODH IC₅₀ = 28.3 ± 3.3 nM) that forms a novel H-bond with Y356. Importantly, compound <b>41</b> possesses significant oral bioavailability (<i>F</i> = 56%) and an elimination <i>t</i>_1/2 = 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