Download MendeleyDesign, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase.
Madak, J.T., Cuthbertson, C.R., Miyata, Y., Tamura, S., Petrunak, E.M., Stuckey, J.A., Han, Y., He, M., Sun, D., Showalter, H.D., Neamati, N.(2018) J Med Chem 61: 5162-5186
- PubMed: 29727569
- DOI: https://doi.org/10.1021/acs.jmedchem.7b01862
- Primary Citation of Related Structures:
6CJF, 6CJG - PubMed Abstract:
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 IC 50 = 9.71 ± 1.4 nM) and 43 (DHODH IC 50 = 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 IC 50 = 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 t 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.
Organizational Affiliation:
Life Sciences Institute and Department of Biological Chemistry , University of Michigan , Ann Arbor , Michigan 48109 , United States.
