TY - JOUR
T1 - Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series
AU - Palmer, Michael J.
AU - Deng, Xiaoyi
AU - Watts, Shawn
AU - Krilov, Goran
AU - Gerasyuto, Aleksey
AU - Kokkonda, Sreekanth
AU - El Mazouni, Farah
AU - White, John
AU - White, Karen L.
AU - Striepen, Josefine
AU - Bath, Jade
AU - Schindler, Kyra A.
AU - Yeo, Tomas
AU - Shackleford, David M.
AU - Mok, Sachel
AU - Deni, Ioanna
AU - Lawong, Aloysus
AU - Huang, Ann
AU - Chen, Gong
AU - Wang, Wen
AU - Jayaseelan, Jaya
AU - Katneni, Kasiram
AU - Patil, Rahul
AU - Saunders, Jessica
AU - Shahi, Shatrughan P.
AU - Chittimalla, Rajesh
AU - Angulo-Barturen, Iñigo
AU - Jiménez-Díaz, María Belén
AU - Wittlin, Sergio
AU - Tumwebaze, Patrick K.
AU - Rosenthal, Philip J.
AU - Cooper, Roland A.
AU - Aguiar, Anna Caroline Campos
AU - Guido, Rafael V.C.
AU - Pereira, Dhelio B.
AU - Mittal, Nimisha
AU - Winzeler, Elizabeth A.
AU - Tomchick, Diana R.
AU - Laleu, Benoît
AU - Burrows, Jeremy N.
AU - Rathod, Pradipsinh K.
AU - Fidock, David A.
AU - Charman, Susan A.
AU - Phillips, Margaret A.
N1 - Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/5/13
Y1 - 2021/5/13
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.1c00173
DO - 10.1021/acs.jmedchem.1c00173
M3 - Article
C2 - 33876936
AN - SCOPUS:85105768750
SN - 0022-2623
VL - 64
SP - 6085
EP - 6136
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 9
ER -