Discovery of a series of 2-(1H-pyrazol-1-yl)pyridines as ALK5 inhibitors with potential utility in the prevention of dermal scarring

Mark L. Boys; Feng Bian; James B. Kramer; Christopher L. Chio; Xiao Dan Ren; Huifen Chen; Stephen D. Barrett; Karen E. Sexton; Donna M. Iula; Gary F. Filzen; Maria N. Nguyen; Paul Angell; Victoria L. Downs; Zhi Wang; Neil Raheja; Edmund L. Ellsworth; Stephen Fakhoury; Larry D. Bratton; Paul R. Keller; Richard Gowan; Elena M. Drummond; Samarendra N. Maiti; Mostofa A. Hena; Leroy Lu; Patrick McConnell; John D. Knafels; Venkataraman Thanabal; Fang Sun; Diane Alessi; Ann McCarthy; Erli Zhang; Barry C. Finzel; Sneha Patel; Susan M. Ciotti; Rone Eisma; N. A. Payne; Richard B. Gilbertsen; Catherine R. Kostlan; David J. Pocalyko; Deepak S. Lala

doi:10.1016/j.bmcl.2012.04.013

Discovery of a series of 2-(1H-pyrazol-1-yl)pyridines as ALK5 inhibitors with potential utility in the prevention of dermal scarring

Mark L. Boys
, Feng Bian
, James B. Kramer
, Christopher L. Chio
, Xiao Dan Ren
, Huifen Chen
, Stephen D. Barrett
, Karen E. Sexton
, Donna M. Iula
, Gary F. Filzen
, Maria N. Nguyen
, Paul Angell
, Victoria L. Downs
, Zhi Wang
, Neil Raheja
, Edmund L. Ellsworth
, Stephen Fakhoury
, Larry D. Bratton
, Paul R. Keller
, Richard Gowan

Elena M. Drummond, Samarendra N. Maiti, Mostofa A. Hena, Leroy Lu, Patrick McConnell, John D. Knafels, Venkataraman Thanabal, Fang Sun, Diane Alessi, Ann McCarthy, Erli Zhang, Barry C. Finzel, Sneha Patel, Susan M. Ciotti, Rone Eisma, N. A. Payne, Richard B. Gilbertsen, Catherine R. Kostlan, David J. Pocalyko, Deepak S. Lala

Medicinal Chemistry

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

11 Scopus citations

Abstract

A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFβ receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFβ induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.

Original language	English (US)
Pages (from-to)	3392-3397
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	10
DOIs	https://doi.org/10.1016/j.bmcl.2012.04.013
State	Published - May 15 2012

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Activin receptor-like Kinase 5
Dermal scarring
Topical
Transforming growth factor beta
Wound repair

Publisher link

10.1016/j.bmcl.2012.04.013

Find It

Find It at U of M Libraries

Cite this

Boys, M. L., Bian, F., Kramer, J. B., Chio, C. L., Ren, X. D., Chen, H., Barrett, S. D., Sexton, K. E., Iula, D. M., Filzen, G. F., Nguyen, M. N., Angell, P., Downs, V. L., Wang, Z., Raheja, N., Ellsworth, E. L., Fakhoury, S., Bratton, L. D., Keller, P. R., ... Lala, D. S. (2012). Discovery of a series of 2-(1H-pyrazol-1-yl)pyridines as ALK5 inhibitors with potential utility in the prevention of dermal scarring. Bioorganic and Medicinal Chemistry Letters, 22(10), 3392-3397. https://doi.org/10.1016/j.bmcl.2012.04.013

Boys, ML, Bian, F, Kramer, JB, Chio, CL, Ren, XD, Chen, H, Barrett, SD, Sexton, KE, Iula, DM, Filzen, GF, Nguyen, MN, Angell, P, Downs, VL, Wang, Z, Raheja, N, Ellsworth, EL, Fakhoury, S, Bratton, LD, Keller, PR, Gowan, R, Drummond, EM, Maiti, SN, Hena, MA, Lu, L, McConnell, P, Knafels, JD, Thanabal, V, Sun, F, Alessi, D, McCarthy, A, Zhang, E, Finzel, BC, Patel, S, Ciotti, SM, Eisma, R, Payne, NA, Gilbertsen, RB, Kostlan, CR, Pocalyko, DJ & Lala, DS 2012, 'Discovery of a series of 2-(1H-pyrazol-1-yl)pyridines as ALK5 inhibitors with potential utility in the prevention of dermal scarring', Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 10, pp. 3392-3397. https://doi.org/10.1016/j.bmcl.2012.04.013

@article{09e488f9d93e4920b868b510755e6886,

title = "Discovery of a series of 2-(1H-pyrazol-1-yl)pyridines as ALK5 inhibitors with potential utility in the prevention of dermal scarring",

abstract = "A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFβ receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFβ induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.",

keywords = "Activin receptor-like Kinase 5, Dermal scarring, Topical, Transforming growth factor beta, Wound repair",

author = "Boys, \{Mark L.\} and Feng Bian and Kramer, \{James B.\} and Chio, \{Christopher L.\} and Ren, \{Xiao Dan\} and Huifen Chen and Barrett, \{Stephen D.\} and Sexton, \{Karen E.\} and Iula, \{Donna M.\} and Filzen, \{Gary F.\} and Nguyen, \{Maria N.\} and Paul Angell and Downs, \{Victoria L.\} and Zhi Wang and Neil Raheja and Ellsworth, \{Edmund L.\} and Stephen Fakhoury and Bratton, \{Larry D.\} and Keller, \{Paul R.\} and Richard Gowan and Drummond, \{Elena M.\} and Maiti, \{Samarendra N.\} and Hena, \{Mostofa A.\} and Leroy Lu and Patrick McConnell and Knafels, \{John D.\} and Venkataraman Thanabal and Fang Sun and Diane Alessi and Ann McCarthy and Erli Zhang and Finzel, \{Barry C.\} and Sneha Patel and Ciotti, \{Susan M.\} and Rone Eisma and Payne, \{N. A.\} and Gilbertsen, \{Richard B.\} and Kostlan, \{Catherine R.\} and Pocalyko, \{David J.\} and Lala, \{Deepak S.\}",

year = "2012",

month = may,

day = "15",

doi = "10.1016/j.bmcl.2012.04.013",

language = "English (US)",

volume = "22",

pages = "3392--3397",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd",

number = "10",

}

TY - JOUR

T1 - Discovery of a series of 2-(1H-pyrazol-1-yl)pyridines as ALK5 inhibitors with potential utility in the prevention of dermal scarring

AU - Boys, Mark L.

AU - Bian, Feng

AU - Kramer, James B.

AU - Chio, Christopher L.

AU - Ren, Xiao Dan

AU - Chen, Huifen

AU - Barrett, Stephen D.

AU - Sexton, Karen E.

AU - Iula, Donna M.

AU - Filzen, Gary F.

AU - Nguyen, Maria N.

AU - Angell, Paul

AU - Downs, Victoria L.

AU - Wang, Zhi

AU - Raheja, Neil

AU - Ellsworth, Edmund L.

AU - Fakhoury, Stephen

AU - Bratton, Larry D.

AU - Keller, Paul R.

AU - Gowan, Richard

AU - Drummond, Elena M.

AU - Maiti, Samarendra N.

AU - Hena, Mostofa A.

AU - Lu, Leroy

AU - McConnell, Patrick

AU - Knafels, John D.

AU - Thanabal, Venkataraman

AU - Sun, Fang

AU - Alessi, Diane

AU - McCarthy, Ann

AU - Zhang, Erli

AU - Finzel, Barry C.

AU - Patel, Sneha

AU - Ciotti, Susan M.

AU - Eisma, Rone

AU - Payne, N. A.

AU - Gilbertsen, Richard B.

AU - Kostlan, Catherine R.

AU - Pocalyko, David J.

AU - Lala, Deepak S.

PY - 2012/5/15

Y1 - 2012/5/15

N2 - A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFβ receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFβ induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.

AB - A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFβ receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFβ induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.

KW - Activin receptor-like Kinase 5

KW - Dermal scarring

KW - Topical

KW - Transforming growth factor beta

KW - Wound repair

UR - https://www.scopus.com/pages/publications/84860459170

UR - https://www.scopus.com/pages/publications/84860459170#tab=citedBy

U2 - 10.1016/j.bmcl.2012.04.013

DO - 10.1016/j.bmcl.2012.04.013

M3 - Article

C2 - 22542194

AN - SCOPUS:84860459170

SN - 0960-894X

VL - 22

SP - 3392

EP - 3397

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 10

ER -

Discovery of a series of 2-(1H-pyrazol-1-yl)pyridines as ALK5 inhibitors with potential utility in the prevention of dermal scarring

Abstract

UN SDGs

Keywords

Publisher link

Find It

Other files and links

Fingerprint

Cite this