2-Benzimidazolyl-9-(chroman-4-yl)-purinone derivatives as JAK3 inhibitors

Andrew G. Cole; Adolph C. Bohnstedt; Vidyadhar Paradkar; Celia Kingsbury; Jorge G. Quintero; Haengsoon Park; Yingchun Lu; Ming You; Irina Neagu; David J. Diller; Jeffrey J. Letourneau; Yuefei Shao; Ray A. James; Christopher M. Riviello; Koc Kan Ho; Tsung H. Lin; Bojing Wang; Kenneth C. Appell; Matthew Sills; Elizabeth Quadros; Earl F. Kimble; Michael H.J. Ohlmeyer; Maria L. Webb

doi:10.1016/j.bmcl.2009.09.080

2-Benzimidazolyl-9-(chroman-4-yl)-purinone derivatives as JAK3 inhibitors

Andrew G. Cole, Adolph C. Bohnstedt, Vidyadhar Paradkar, Celia Kingsbury, Jorge G. Quintero, Haengsoon Park, Yingchun Lu, Ming You, Irina Neagu, David J. Diller, Jeffrey J. Letourneau, Yuefei Shao, Ray A. James, Christopher M. Riviello, Koc Kan Ho, Tsung H. Lin, Bojing Wang, Kenneth C. Appell, Matthew Sills, Elizabeth QuadrosEarl F. Kimble, Michael H.J. Ohlmeyer, Maria L. Webb

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

14 Scopus citations

Abstract

A novel class of Janus tyrosine kinase 3 (JAK3) inhibitors based on a 2-benzimidazoylpurinone core structure is described. Through substitution of the benzimidazoyl moiety and optimization of the N-9 substituent of the purinone, compound 24 was identified incorporating a chroman-based functional group. Compound 24 shows excellent kinase activity, good oral bioavailability and demonstrates efficacy in an acute mechanistic mouse model through inhibition of interleukin-2 (IL-2) induced interferon-γ (INF-γ) production.

Original language	English
Pages (from-to)	6788-6792
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	19
Issue number	23
DOIs	https://doi.org/10.1016/j.bmcl.2009.09.080
State	Published - 1 Dec 2009
Externally published	Yes

Keywords

Benzimidazole
Chroman
JAK3
Janus kinase
Purinone
Rheumatoid arthritis

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10.1016/j.bmcl.2009.09.080

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Cole, A. G., Bohnstedt, A. C., Paradkar, V., Kingsbury, C., Quintero, J. G., Park, H., Lu, Y., You, M., Neagu, I., Diller, D. J., Letourneau, J. J., Shao, Y., James, R. A., Riviello, C. M., Ho, K. K., Lin, T. H., Wang, B., Appell, K. C., Sills, M., ... Webb, M. L. (2009). 2-Benzimidazolyl-9-(chroman-4-yl)-purinone derivatives as JAK3 inhibitors. Bioorganic and Medicinal Chemistry Letters, 19(23), 6788-6792. https://doi.org/10.1016/j.bmcl.2009.09.080

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title = "2-Benzimidazolyl-9-(chroman-4-yl)-purinone derivatives as JAK3 inhibitors",

abstract = "A novel class of Janus tyrosine kinase 3 (JAK3) inhibitors based on a 2-benzimidazoylpurinone core structure is described. Through substitution of the benzimidazoyl moiety and optimization of the N-9 substituent of the purinone, compound 24 was identified incorporating a chroman-based functional group. Compound 24 shows excellent kinase activity, good oral bioavailability and demonstrates efficacy in an acute mechanistic mouse model through inhibition of interleukin-2 (IL-2) induced interferon-γ (INF-γ) production.",

keywords = "Benzimidazole, Chroman, JAK3, Janus kinase, Purinone, Rheumatoid arthritis",

author = "Cole, {Andrew G.} and Bohnstedt, {Adolph C.} and Vidyadhar Paradkar and Celia Kingsbury and Quintero, {Jorge G.} and Haengsoon Park and Yingchun Lu and Ming You and Irina Neagu and Diller, {David J.} and Letourneau, {Jeffrey J.} and Yuefei Shao and James, {Ray A.} and Riviello, {Christopher M.} and Ho, {Koc Kan} and Lin, {Tsung H.} and Bojing Wang and Appell, {Kenneth C.} and Matthew Sills and Elizabeth Quadros and Kimble, {Earl F.} and Ohlmeyer, {Michael H.J.} and Webb, {Maria L.}",

year = "2009",

month = dec,

day = "1",

doi = "10.1016/j.bmcl.2009.09.080",

language = "English",

volume = "19",

pages = "6788--6792",

journal = "Bioorganic and Medicinal Chemistry Letters",

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number = "23",

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Cole, AG, Bohnstedt, AC, Paradkar, V, Kingsbury, C, Quintero, JG, Park, H, Lu, Y, You, M, Neagu, I, Diller, DJ, Letourneau, JJ, Shao, Y, James, RA, Riviello, CM, Ho, KK, Lin, TH, Wang, B, Appell, KC, Sills, M, Quadros, E, Kimble, EF, Ohlmeyer, MHJ & Webb, ML 2009, '2-Benzimidazolyl-9-(chroman-4-yl)-purinone derivatives as JAK3 inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 23, pp. 6788-6792. https://doi.org/10.1016/j.bmcl.2009.09.080

TY - JOUR

T1 - 2-Benzimidazolyl-9-(chroman-4-yl)-purinone derivatives as JAK3 inhibitors

AU - Cole, Andrew G.

AU - Bohnstedt, Adolph C.

AU - Paradkar, Vidyadhar

AU - Kingsbury, Celia

AU - Quintero, Jorge G.

AU - Park, Haengsoon

AU - Lu, Yingchun

AU - You, Ming

AU - Neagu, Irina

AU - Diller, David J.

AU - Letourneau, Jeffrey J.

AU - Shao, Yuefei

AU - James, Ray A.

AU - Riviello, Christopher M.

AU - Ho, Koc Kan

AU - Lin, Tsung H.

AU - Wang, Bojing

AU - Appell, Kenneth C.

AU - Sills, Matthew

AU - Quadros, Elizabeth

AU - Kimble, Earl F.

AU - Ohlmeyer, Michael H.J.

AU - Webb, Maria L.

PY - 2009/12/1

Y1 - 2009/12/1

N2 - A novel class of Janus tyrosine kinase 3 (JAK3) inhibitors based on a 2-benzimidazoylpurinone core structure is described. Through substitution of the benzimidazoyl moiety and optimization of the N-9 substituent of the purinone, compound 24 was identified incorporating a chroman-based functional group. Compound 24 shows excellent kinase activity, good oral bioavailability and demonstrates efficacy in an acute mechanistic mouse model through inhibition of interleukin-2 (IL-2) induced interferon-γ (INF-γ) production.

AB - A novel class of Janus tyrosine kinase 3 (JAK3) inhibitors based on a 2-benzimidazoylpurinone core structure is described. Through substitution of the benzimidazoyl moiety and optimization of the N-9 substituent of the purinone, compound 24 was identified incorporating a chroman-based functional group. Compound 24 shows excellent kinase activity, good oral bioavailability and demonstrates efficacy in an acute mechanistic mouse model through inhibition of interleukin-2 (IL-2) induced interferon-γ (INF-γ) production.

KW - Benzimidazole

KW - Chroman

KW - JAK3

KW - Janus kinase

KW - Purinone

KW - Rheumatoid arthritis

UR - http://www.scopus.com/inward/record.url?scp=71749088434&partnerID=8YFLogxK

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DO - 10.1016/j.bmcl.2009.09.080

M3 - Article

C2 - 19836234

AN - SCOPUS:71749088434

SN - 0960-894X

VL - 19

SP - 6788

EP - 6792

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 23

ER -

2-Benzimidazolyl-9-(chroman-4-yl)-purinone derivatives as JAK3 inhibitors

Abstract

Keywords

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