Binding mode and potency of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors targeting Trypanosoma cruzi CYP51

Vieira, Debora F.; Choi, Jun Yong; Calvet, Claudia M.; Siqueira-Neto, Jair Lage; Johnston, Jonathan B.; Kellar, Danielle; Gut, Jiri; Cameron, Michael D.; McKerrow, James H.; Roush, William R.; Podust, Larissa M.

doi:10.1021/jm501568b

Title: Binding mode and potency of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors targeting Trypanosoma cruzi CYP51

Journal Article · Thu Nov 13 00:00:00 EST 2014 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/jm501568b· OSTI ID:1346023

Vieira, Debora F. ^[1]; Choi, Jun Yong ^[2]; Calvet, Claudia M. ^[3]; Siqueira-Neto, Jair Lage ^[4]; Johnston, Jonathan B. ^[1]; Kellar, Danielle ^[5]; Gut, Jiri ^[1]; Cameron, Michael D. ^[2]; McKerrow, James H. ^[4]; Roush, William R. ^[2]; Podust, Larissa M. ^[4]

Univ. of California, San Francisco, CA (United States)
Scripps Florida, Jupiter, FL (United States)
Oswaldo Cruz Institute (IOC), Rio de Janeiro (Brazil)
Univ. of California, San Francisco, CA (United States); Univ. of California - San Diego, La Jolla, CA (United States)
Univ. of California, San Francisco, CA (United States); Five Prime Therapeutics, San Francisco, CA (United States)

Chagas disease is a chronic infection in humans caused by Trypanosoma cruzi and manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Limited therapeutic options to prevent and treat Chagas disease put 8 million people infected with T. cruzi worldwide at risk. CYP51, involved in the biosynthesis of the membrane sterol component in eukaryotes, is a promising drug target in T. cruzi. We report the structure–activity relationships (SAR) of an N-arylpiperazine series of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors designed to probe the impact of substituents in the terminal N-phenyl ring on binding mode, selectivity and potency. Depending on the substituents at C-4, two distinct ring binding modes, buried and solvent-exposed, have been observed by X-ray structure analysis (resolution of 1.95–2.48 Å). Lastly, the 5-chloro-substituted analogs 9 and 10 with no substituent at C-4 demonstrated improved selectivity and potency, suppressing ≥99.8% parasitemia in mice when administered orally at 25 mg/kg, b.i.d., for 4 days.

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Research Organization:: Univ. of California, San Francisco, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1346023

Journal Information:: Journal of Medicinal Chemistry, Vol. 57, Issue 23; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 20 works

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Title: Binding mode and potency of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors targeting Trypanosoma cruzi CYP51

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