title: Scaffold hopping towards potent and selective JAK3 inhibitors: discovery of novel C-5 substituted pyrrolopyrazines.
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.
authors.affiliation: 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.
authors.forename: Javier
authors.initials: J
authors.lastname: de Vicente
authors.affiliation: Roche Palo Alto, 3401 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Remy
authors.initials: R
authors.lastname: Lemoine
authors.affiliation: Roche Palo Alto, 3401 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Bartlett
authors.affiliation: Small Molecule Research, Pharma Research & Early Development, pRED, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Hermann
authors.affiliation: Roche Palo Alto, 3401 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hekmat-Nejad
authors.affiliation: Roche Palo Alto, 3401 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Henningsen
authors.affiliation: Small Molecule Research, Pharma Research & Early Development, pRED, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Sue
authors.initials: S
authors.lastname: Jin
authors.affiliation: Small Molecule Research, Pharma Research & Early Development, pRED, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuglstatter
authors.affiliation: Small Molecule Research, Pharma Research & Early Development, pRED, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Hongju
authors.initials: H
authors.lastname: Li
authors.affiliation: Small Molecule Research, Pharma Research & Early Development, pRED, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Lovey
authors.affiliation: Small Molecule Research, Pharma Research & Early Development, pRED, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: John
authors.initials: J
authors.lastname: Menke
authors.affiliation: Small Molecule Research, Pharma Research & Early Development, pRED, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Linghao
authors.initials: L
authors.lastname: Niu
authors.affiliation: Small Molecule Research, Pharma Research & Early Development, pRED, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Patel
authors.affiliation: Small Molecule Research, Pharma Research & Early Development, pRED, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Ann
authors.initials: A
authors.lastname: Petersen
authors.affiliation: Roche Palo Alto, 3401 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Lina
authors.initials: L
authors.lastname: Setti
authors.affiliation: Roche Palo Alto, 3401 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Ada
authors.initials: A
authors.lastname: Shao
authors.affiliation: Small Molecule Research, Pharma Research & Early Development, pRED, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Parcharee
authors.initials: P
authors.lastname: Tivitmahaisoon
authors.affiliation: Small Molecule Research, Pharma Research & Early Development, pRED, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Minh Diem
authors.initials: MD
authors.lastname: Vu
authors.affiliation: Small Molecule Research, Pharma Research & Early Development, pRED, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Soth
mesh_terms: D015195:Drug Design; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011719:Pyrazines / Q000737:chemistry*; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D053616:Janus Kinase 3
keywords: Intramolecular hydrogen bond; JAK; Janus kinase; Kinase inhibitors; Scaffold hopping; Structure based drug design