title: 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.
abstract: 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.
authors.affiliation: Roche Palo Alto LLC, 3431 Hillview Avenue, R6-123, Palo Alto, California 94304, USA. David-M.Goldstein@roche.com
authors.forename: David M
authors.initials: DM
authors.lastname: Goldstein
authors.forename: Tom
authors.initials: T
authors.lastname: Alfredson
authors.forename: Jay
authors.initials: J
authors.lastname: Bertrand
authors.forename: Michelle F
authors.initials: MF
authors.lastname: Browner
authors.forename: Ken
authors.initials: K
authors.lastname: Clifford
authors.forename: Stacie A
authors.initials: SA
authors.lastname: Dalrymple
authors.forename: James
authors.initials: J
authors.lastname: Dunn
authors.forename: Jose
authors.initials: J
authors.lastname: Freire-Moar
authors.forename: Seth
authors.initials: S
authors.lastname: Harris
authors.forename: Sharada S
authors.initials: SS
authors.lastname: Labadie
authors.forename: JoAnn
authors.initials: J
authors.lastname: La Fargue
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Lapierre
authors.forename: Susan
authors.initials: S
authors.lastname: Larrabee
authors.forename: Fujun
authors.initials: F
authors.lastname: Li
authors.forename: Eva
authors.initials: E
authors.lastname: Papp
authors.forename: Daniel
authors.initials: D
authors.lastname: McWeeney
authors.forename: Chakk
authors.initials: C
authors.lastname: Ramesha
authors.forename: Rick
authors.initials: R
authors.lastname: Roberts
authors.forename: David
authors.initials: D
authors.lastname: Rotstein
authors.forename: Bong
authors.initials: B
authors.lastname: San Pablo
authors.forename: Eric B
authors.initials: EB
authors.lastname: Sjogren
authors.forename: On-Yee
authors.initials: OY
authors.lastname: So
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Talamas
authors.forename: Will
authors.initials: W
authors.lastname: Tao
authors.forename: Alejandra
authors.initials: A
authors.lastname: Trejo
authors.forename: Armando
authors.initials: A
authors.lastname: Villasenor
authors.forename: Mary
authors.initials: M
authors.lastname: Welch
authors.forename: Teresa
authors.initials: T
authors.lastname: Welch
authors.forename: Paul
authors.initials: P
authors.lastname: Weller
authors.forename: Phyllis E
authors.initials: PE
authors.lastname: Whiteley
authors.forename: Kelly
authors.initials: K
authors.lastname: Young
authors.forename: Sheila
authors.initials: S
authors.lastname: Zipfel
mesh_terms: 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
chemical_list: 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