Discovery of 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2-(R) -methylpiperazine (BMS-378806): A novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions

Tao Wang; Zhongxing Zhang; Owen B. Wallace; Milind Deshpande; Haiquan Fang; Zheng Yang; Lisa M. Zadjura; Donald L. Tweedie; Stella Huang; Fang Zhao; Sunanda Ranadive; Brett S. Robinson; Yi Fei Gong; Keith Ricarrdi; Timothy P. Spicer; Carol Deminie; Ronald Rose; Hwei Gene Heidi Wang; Wade S. Blair; Pei Yong Shi; Pin Fang Lin; Richard J. Colonno; Nicholas A. Meanwell

doi:10.1021/jm034082o

Discovery of 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2-(R) -methylpiperazine (BMS-378806): A novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions

Tao Wang, Zhongxing Zhang, Owen B. Wallace, Milind Deshpande, Haiquan Fang, Zheng Yang, Lisa M. Zadjura, Donald L. Tweedie, Stella Huang, Fang Zhao, Sunanda Ranadive, Brett S. Robinson, Yi Fei Gong, Keith Ricarrdi, Timothy P. Spicer, Carol Deminie, Ronald Rose, Hwei Gene Heidi Wang, Wade S. Blair, Pei Yong ShiPin Fang Lin, Richard J. Colonno, Nicholas A. Meanwell

Biochemistry & Molecular Biology

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

225 Scopus citations

Abstract

Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.

Original language	English (US)
Pages (from-to)	4236-4239
Number of pages	4
Journal	Journal of medicinal chemistry
Volume	46
Issue number	20
DOIs	https://doi.org/10.1021/jm034082o
State	Published - Sep 25 2003

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/jm034082o

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Wang, T., Zhang, Z., Wallace, O. B., Deshpande, M., Fang, H., Yang, Z., Zadjura, L. M., Tweedie, D. L., Huang, S., Zhao, F., Ranadive, S., Robinson, B. S., Gong, Y. F., Ricarrdi, K., Spicer, T. P., Deminie, C., Rose, R., Wang, H. G. H., Blair, W. S., ... Meanwell, N. A. (2003). Discovery of 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2-(R) -methylpiperazine (BMS-378806): A novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions. Journal of medicinal chemistry, 46(20), 4236-4239. https://doi.org/10.1021/jm034082o

Discovery of 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2-(R) -methylpiperazine (BMS-378806): A novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions. / Wang, Tao; Zhang, Zhongxing; Wallace, Owen B. et al.
In: Journal of medicinal chemistry, Vol. 46, No. 20, 25.09.2003, p. 4236-4239.

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

Wang, T, Zhang, Z, Wallace, OB, Deshpande, M, Fang, H, Yang, Z, Zadjura, LM, Tweedie, DL, Huang, S, Zhao, F, Ranadive, S, Robinson, BS, Gong, YF, Ricarrdi, K, Spicer, TP, Deminie, C, Rose, R, Wang, HGH, Blair, WS, Shi, PY, Lin, PF, Colonno, RJ & Meanwell, NA 2003, 'Discovery of 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2-(R) -methylpiperazine (BMS-378806): A novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions', Journal of medicinal chemistry, vol. 46, no. 20, pp. 4236-4239. https://doi.org/10.1021/jm034082o

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title = "Discovery of 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2-(R) -methylpiperazine (BMS-378806): A novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions",

abstract = "Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.",

author = "Tao Wang and Zhongxing Zhang and Wallace, \{Owen B.\} and Milind Deshpande and Haiquan Fang and Zheng Yang and Zadjura, \{Lisa M.\} and Tweedie, \{Donald L.\} and Stella Huang and Fang Zhao and Sunanda Ranadive and Robinson, \{Brett S.\} and Gong, \{Yi Fei\} and Keith Ricarrdi and Spicer, \{Timothy P.\} and Carol Deminie and Ronald Rose and Wang, \{Hwei Gene Heidi\} and Blair, \{Wade S.\} and Shi, \{Pei Yong\} and Lin, \{Pin Fang\} and Colonno, \{Richard J.\} and Meanwell, \{Nicholas A.\}",

year = "2003",

month = sep,

day = "25",

doi = "10.1021/jm034082o",

language = "English (US)",

volume = "46",

pages = "4236--4239",

journal = "Journal of medicinal chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "20",

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T1 - Discovery of 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2-(R) -methylpiperazine (BMS-378806)

T2 - A novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions

AU - Wang, Tao

AU - Zhang, Zhongxing

AU - Wallace, Owen B.

AU - Deshpande, Milind

AU - Fang, Haiquan

AU - Yang, Zheng

AU - Zadjura, Lisa M.

AU - Tweedie, Donald L.

AU - Huang, Stella

AU - Zhao, Fang

AU - Ranadive, Sunanda

AU - Robinson, Brett S.

AU - Gong, Yi Fei

AU - Ricarrdi, Keith

AU - Spicer, Timothy P.

AU - Deminie, Carol

AU - Rose, Ronald

AU - Wang, Hwei Gene Heidi

AU - Blair, Wade S.

AU - Shi, Pei Yong

AU - Lin, Pin Fang

AU - Colonno, Richard J.

AU - Meanwell, Nicholas A.

PY - 2003/9/25

Y1 - 2003/9/25

N2 - Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.

AB - Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.

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Discovery of 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2-(R) -methylpiperazine (BMS-378806): A novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions

Abstract

ASJC Scopus subject areas

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