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Your search keyword '"Chittimalla R"' showing total 2 results
Start Over Author "Chittimalla R" Topic pyrroles
2 results on '"Chittimalla R"'

1. Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.

Author

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, Jiménez-Díaz 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, and Phillips MA

Subjects
Animals, Antimalarials chemistry, Dihydroorotate Dehydrogenase, Enzyme Inhibitors chemistry, Mice, Plasmodium falciparum drug effects, Pyrroles chemistry, Structure-Activity Relationship, Antimalarials pharmacology, Drug Design, Enzyme Inhibitors pharmacology, Oxidoreductases Acting on CH-CH Group Donors antagonists & inhibitors, Pyrroles pharmacology
Abstract

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.

Published
2021
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2. Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria.

Author

Kokkonda S, Deng X, White KL, El Mazouni F, White J, Shackleford DM, Katneni K, Chiu FCK, Barker H, McLaren J, Crighton E, Chen G, Angulo-Barturen I, Jimenez-Diaz MB, Ferrer S, Huertas-Valentin L, Martinez-Martinez MS, Lafuente-Monasterio MJ, Chittimalla R, Shahi SP, Wittlin S, Waterson D, Burrows JN, Matthews D, Tomchick D, Rathod PK, Palmer MJ, Charman SA, and Phillips MA

Subjects
Animals, Antimalarials chemical synthesis, Antimalarials metabolism, Antimalarials pharmacokinetics, Cell Line, Tumor, Crystallography, X-Ray, Dihydroorotate Dehydrogenase, Dogs, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacokinetics, Female, Humans, Male, Mice, SCID, Microsomes, Liver metabolism, Molecular Structure, Oxidoreductases Acting on CH-CH Group Donors metabolism, Parasitic Sensitivity Tests, Plasmodium falciparum drug effects, Plasmodium falciparum enzymology, Plasmodium vivax drug effects, Plasmodium vivax enzymology, Protein Binding, Pyrroles chemical synthesis, Pyrroles metabolism, Pyrroles pharmacokinetics, Rats, Structure-Activity Relationship, Antimalarials therapeutic use, Enzyme Inhibitors therapeutic use, Malaria, Falciparum drug therapy, Oxidoreductases Acting on CH-CH Group Donors antagonists & inhibitors, Pyrroles therapeutic use
Abstract

Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 ( 1 ) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 ( 37 ) showed in vivo efficacy at similar levels of blood exposure to 1 , although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.

Published
2020
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