Discovery of S-[5-amino-1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[3-(2,3-dihydroxypropoxy)phenyl]methanone (RO3201195), an orally bioavailable and highly selective inhibitor of p38 MAP kinase.
A novel class of highly selective inhibitors of p38 MAP kinase was discovered from high throughput screening. The synthesis and optimization of a series of 5-amino-N-phenyl-1H-pyrazol-4-yl-3-phenylmethanones is described. An X-ray crystal structure of this series bound in the ATP binding pocket of unphosphorylated p38alpha established the presence of a unique hydrogen bond between the exocyclic amine of the inhibitor and threonine 106 which likely contributes to the selectivity for p38. The crystallographic information was used to optimize the potency and physicochemical properties of the series. The incorporation of the 2,3-dihydroxypropoxy moiety on the pyrazole scaffold resulted in a compound with excellent drug-like properties including high oral bioavailability. These efforts identified 63 (RO3201195) as an orally bioavailable and highly selective inhibitor of p38 which was selected for advancement into Phase I clinical trials.
Goldstein
David M
DM
Roche Palo Alto LLC, 3431 Hillview Avenue, R6-123, Palo Alto, California 94304, USA. David-M.Goldstein@roche.com
Alfredson
Tom
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Bertrand
Jay
J
Browner
Michelle F
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Clifford
Ken
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Dalrymple
Stacie A
SA
Dunn
James
J
Freire-Moar
Jose
J
Harris
Seth
S
Labadie
Sharada S
SS
La Fargue
JoAnn
J
Lapierre
Jean Marc
JM
Larrabee
Susan
S
Li
Fujun
F
Papp
Eva
E
McWeeney
Daniel
D
Ramesha
Chakk
C
Roberts
Rick
R
Rotstein
David
D
San Pablo
Bong
B
Sjogren
Eric B
EB
So
On-Yee
OY
Talamas
Francisco X
FX
Tao
Will
W
Trejo
Alejandra
A
Villasenor
Armando
A
Welch
Mary
M
Welch
Teresa
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Weller
Paul
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Whiteley
Phyllis E
PE
Young
Kelly
K
Zipfel
Sheila
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D000255:Adenosine Triphosphate / Q000737:chemistry; D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D001665:Binding Sites; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D005260:Female; D000882:Haplorhini; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000093242:Interleukin-6 Inhibitors
D000255:Adenosine Triphosphate; D000893:Anti-Inflammatory Agents; D007375:Interleukin-1; D015850:Interleukin-6; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; C509704:5-amino-1-(4-fluorophenyl)-4-(3-(2,3-dihydroxypropoxy)benzoyl)pyrazole