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Publication Abstract from PubMed

Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes.

Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.,Palmer MJ, Deng X, Watts S, Krilov G, Gerasyuto A, Kokkonda S, El Mazouni F, White J, White KL, Striepen J, Bath J, Schindler KA, Yeo T, Shackleford DM, Mok S, Deni I, Lawong A, Huang A, Chen G, Wang W, Jayaseelan J, Katneni K, Patil R, Saunders J, Shahi SP, Chittimalla R, Angulo-Barturen I, Jimenez-Diaz MB, Wittlin S, Tumwebaze PK, Rosenthal PJ, Cooper RA, Aguiar ACC, Guido RVC, Pereira DB, Mittal N, Winzeler EA, Tomchick DR, Laleu B, Burrows JN, Rathod PK, Fidock DA, Charman SA, Phillips MA J Med Chem. 2021 May 13;64(9):6085-6136. doi: 10.1021/acs.jmedchem.1c00173. Epub , 2021 Apr 20. PMID:33876936^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.