Lead optimization of spiropyrazolopyridones: A new and potent class of dengue virus inhibitors

Bin Zou; Wai Ling Chan; Mei Ding; Seh Yong Leong; Shahul Nilar; Peck Gee Seah; Wei Liu; Ratna Karuna; Francesca Blasco; Andy Yip; Alex Chao; Agatha Susila; Hongping Dong; Qing Yin Wang; Hao Ying Xu; Katherine Chan; Kah Fei Wan; Feng Gu; Thierry T. Diagana; Trixie Wagner; Ina Dix; Pei Yong Shi; Paul W. Smith

doi:10.1021/ml500521r

Lead optimization of spiropyrazolopyridones: A new and potent class of dengue virus inhibitors

Bin Zou, Wai Ling Chan, Mei Ding, Seh Yong Leong, Shahul Nilar, Peck Gee Seah, Wei Liu, Ratna Karuna, Francesca Blasco, Andy Yip, Alex Chao, Agatha Susila, Hongping Dong, Qing Yin Wang, Hao Ying Xu, Katherine Chan, Kah Fei Wan, Feng Gu, Thierry T. Diagana, Trixie WagnerIna Dix, Pei Yong Shi, Paul W. Smith

Biochemistry & Molecular Biology

Research output: Contribution to journal › Article › peer-review

63 Scopus citations

Abstract

Spiropyrazolopyridone 1 was identified, as a novel dengue virus (DENV) inhibitor, from a DENV serotype 2 (DENV-2) high-throughput phenotypic screen. As a general trend within this chemical class, chiral resolution of the racemate revealed that R enantiomer was significantly more potent than the S. Cell-based lead optimization of the spiropyrazolopyridones focusing on improving the physicochemical properties is described. As a result, an optimal compound 14a, with balanced in vitro potency and pharmacokinetic profile, achieved about 1.9 log viremia reduction at 3 × 50 mg/kg (bid) or 3 × 100 mg/kg (QD) oral doses in the dengue in vivo mouse efficacy model.

Original language	English (US)
Pages (from-to)	344-348
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	6
Issue number	3
DOIs	https://doi.org/10.1021/ml500521r
State	Published - Mar 12 2015

Keywords

Dengue virus (DENV)
lead optimization
spiropyrazolopyridones
structure-activity relationship

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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Zou, B., Chan, W. L., Ding, M., Leong, S. Y., Nilar, S., Seah, P. G., Liu, W., Karuna, R., Blasco, F., Yip, A., Chao, A., Susila, A., Dong, H., Wang, Q. Y., Xu, H. Y., Chan, K., Wan, K. F., Gu, F., Diagana, T. T., ... Smith, P. W. (2015). Lead optimization of spiropyrazolopyridones: A new and potent class of dengue virus inhibitors. ACS Medicinal Chemistry Letters, 6(3), 344-348. https://doi.org/10.1021/ml500521r

Zou, B, Chan, WL, Ding, M, Leong, SY, Nilar, S, Seah, PG, Liu, W, Karuna, R, Blasco, F, Yip, A, Chao, A, Susila, A, Dong, H, Wang, QY, Xu, HY, Chan, K, Wan, KF, Gu, F, Diagana, TT, Wagner, T, Dix, I, Shi, PY & Smith, PW 2015, 'Lead optimization of spiropyrazolopyridones: A new and potent class of dengue virus inhibitors', ACS Medicinal Chemistry Letters, vol. 6, no. 3, pp. 344-348. https://doi.org/10.1021/ml500521r

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title = "Lead optimization of spiropyrazolopyridones: A new and potent class of dengue virus inhibitors",

abstract = "Spiropyrazolopyridone 1 was identified, as a novel dengue virus (DENV) inhibitor, from a DENV serotype 2 (DENV-2) high-throughput phenotypic screen. As a general trend within this chemical class, chiral resolution of the racemate revealed that R enantiomer was significantly more potent than the S. Cell-based lead optimization of the spiropyrazolopyridones focusing on improving the physicochemical properties is described. As a result, an optimal compound 14a, with balanced in vitro potency and pharmacokinetic profile, achieved about 1.9 log viremia reduction at 3 × 50 mg/kg (bid) or 3 × 100 mg/kg (QD) oral doses in the dengue in vivo mouse efficacy model.",

keywords = "Dengue virus (DENV), lead optimization, spiropyrazolopyridones, structure-activity relationship",

author = "Bin Zou and Chan, {Wai Ling} and Mei Ding and Leong, {Seh Yong} and Shahul Nilar and Seah, {Peck Gee} and Wei Liu and Ratna Karuna and Francesca Blasco and Andy Yip and Alex Chao and Agatha Susila and Hongping Dong and Wang, {Qing Yin} and Xu, {Hao Ying} and Katherine Chan and Wan, {Kah Fei} and Feng Gu and Diagana, {Thierry T.} and Trixie Wagner and Ina Dix and Shi, {Pei Yong} and Smith, {Paul W.}",

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doi = "10.1021/ml500521r",

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AU - Nilar, Shahul

AU - Seah, Peck Gee

AU - Liu, Wei

AU - Karuna, Ratna

AU - Blasco, Francesca

AU - Yip, Andy

AU - Chao, Alex

AU - Susila, Agatha

AU - Dong, Hongping

AU - Wang, Qing Yin

AU - Xu, Hao Ying

AU - Chan, Katherine

AU - Wan, Kah Fei

AU - Gu, Feng

AU - Diagana, Thierry T.

AU - Wagner, Trixie

AU - Dix, Ina

AU - Shi, Pei Yong

AU - Smith, Paul W.

PY - 2015/3/12

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AB - Spiropyrazolopyridone 1 was identified, as a novel dengue virus (DENV) inhibitor, from a DENV serotype 2 (DENV-2) high-throughput phenotypic screen. As a general trend within this chemical class, chiral resolution of the racemate revealed that R enantiomer was significantly more potent than the S. Cell-based lead optimization of the spiropyrazolopyridones focusing on improving the physicochemical properties is described. As a result, an optimal compound 14a, with balanced in vitro potency and pharmacokinetic profile, achieved about 1.9 log viremia reduction at 3 × 50 mg/kg (bid) or 3 × 100 mg/kg (QD) oral doses in the dengue in vivo mouse efficacy model.

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Lead optimization of spiropyrazolopyridones: A new and potent class of dengue virus inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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