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 & 3 others Pin Fang Lin, Richard J. Colonno, Nicholas A. Meanwell

Research output: Contribution to journalArticle

175 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)4236-4239
Number of pages4
JournalJournal of Medicinal Chemistry
Volume46
Issue number20
DOIs
StatePublished - Sep 25 2003
Externally publishedYes

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Human Immunodeficiency Virus Proteins
CD4 Antigens
Macaca fascicularis
HIV-1
Suspensions
Membrane Proteins
Dogs
Derivatives
Pharmaceutical Preparations
Rats
Dissolution
7-azaindole dimer
indole
BMS-378806

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

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

In: Journal of Medicinal Chemistry, Vol. 46, No. 20, 25.09.2003, p. 4236-4239.

Research output: Contribution to journalArticle

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, P-Y, 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
Wang, Tao ; Zhang, Zhongxing ; Wallace, Owen B. ; Deshpande, Milind ; Fang, Haiquan ; Yang, Zheng ; Zadjura, Lisa M. ; Tweedie, Donald L. ; Huang, Stella ; Zhao, Fang ; Ranadive, Sunanda ; Robinson, Brett S. ; Gong, Yi Fei ; Ricarrdi, Keith ; Spicer, Timothy P. ; Deminie, Carol ; Rose, Ronald ; Wang, Hwei Gene Heidi ; Blair, Wade S. ; Shi, Pei-Yong ; Lin, Pin Fang ; Colonno, Richard J. ; Meanwell, Nicholas A. / 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. In: Journal of Medicinal Chemistry. 2003 ; Vol. 46, No. 20. pp. 4236-4239.
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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.",
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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

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