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Bioorg Med Chem Lett. 2017 May 1;27(9):1955-1961. doi: 10.1016/j.bmcl.2017.03.026. Epub 2017 Mar 14.

Design, synthesis and optimization of 7-substituted-pyrazolo[4,3-b]pyridine ALK5 (activin receptor-like kinase 5) inhibitors.

Author information

1
Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States. Electronic address: mark.sabat@takedasd.com.
2
Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.

Abstract

A series of potent ALK5 inhibitors were designed using a SBDD approach and subsequently optimized to improve drug likeness. Starting with a 4-substituted quinoline screening hit, SAR was conducted using a ALK5 binding model to understand the binding site and optimize activity. The resulting inhibitors displayed excellent potency but were limited by high in vitro clearance in rat and human microsomes. Using a scaffold morphing strategy, these analogs were transformed into a related pyrazolo[4,3-b]pyridine series with improved ADME properties.

KEYWORDS:

ALK5 activin-like kinase 5

PMID:
28359790
DOI:
10.1016/j.bmcl.2017.03.026
[Indexed for MEDLINE]

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