Pyrrolopyrazines as selective spleen tyrosine kinase inhibitors.
We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.
Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
Fernando
F
Padilla
Niala
N
Bhagirath
Shaoqing
S
Chen
Eric
E
Chiao
David M
DM
Goldstein
Johannes C
JC
Hermann
Jonathan
J
Hsu
Joshua J
JJ
Kennedy-Smith
Andreas
A
Kuglstatter
Cheng
C
Liao
Wenjian
W
Liu
Lee E
LE
Lowrie
Kin Chun
KC
Luk
Stephen M
SM
Lynch
John
J
Menke
Linghao
L
Niu
Timothy D
TD
Owens
Counde
C
O-Yang
Aruna
A
Railkar
Ryan C
RC
Schoenfeld
Michelle
M
Slade
Sandra
S
Steiner
Yun-Chou
YC
Tan
Armando G
AG
Villaseñor
Ce
C
Wang
Jutta
J
Wanner
Wenwei
W
Xie
Daigen
D
Xu
Xiaohu
X
Zhang
Mingyan
M
Zhou
Matthew C
MC
Lucas
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology; D001798:Blood Proteins / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D000072377:Syk Kinase
D001798:Blood Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011719:Pyrazines; D011758:Pyrroles; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse