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Bioorg Med Chem Lett. 2014 Nov 1;24(21):4969-75. doi: 10.1016/j.bmcl.2014.09.031. Epub 2014 Sep 21.

Scaffold hopping towards potent and selective JAK3 inhibitors: discovery of novel C-5 substituted pyrrolopyrazines.

Author information

1
Small Molecule Research, Pharma Research & Early Development, pRED, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States. Electronic address: javier.devicente@novartis.com.
2
Roche Palo Alto, 3401 Hillview Ave, Palo Alto, CA 94304, United States.
3
Small Molecule Research, Pharma Research & Early Development, pRED, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.

Abstract

The discovery of a novel series of pyrrolopyrazines as JAK inhibitors with comparable enzyme and cellular activity to tofacitinib is described. The series was identified using a scaffold hopping approach aided by structure based drug design using principles of intramolecular hydrogen bonding for conformational restriction and targeting specific pockets for modulating kinase activity.

KEYWORDS:

Intramolecular hydrogen bond; JAK; Janus kinase; Kinase inhibitors; Scaffold hopping; Structure based drug design

PMID:
25262541
DOI:
10.1016/j.bmcl.2014.09.031
[Indexed for MEDLINE]

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