title: Design and synthesis of 4-azaindoles as inhibitors of p38 MAP kinase.
abstract: Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b] pyridine, is described. X-ray crystallographic data of the lead bound to the active site of p38 was used to guide the optimization of the series. Specific focus was placed on modulating the physical properties of the core while maintaining potent inhibition of p38. These efforts identified 42c as a potent inhibitor of p38, which also possessed the required physical properties worthy of advanced studies.
authors.affiliation: Department of Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, R6-201, Palo Alto, California 94304, USA. alejandro.trejo@roche.com
authors.forename: Alejandra
authors.initials: A
authors.lastname: Trejo
authors.forename: Humberto
authors.initials: H
authors.lastname: Arzeno
authors.forename: Michelle
authors.initials: M
authors.lastname: Browner
authors.forename: Sushmita
authors.initials: S
authors.lastname: Chanda
authors.forename: Soan
authors.initials: S
authors.lastname: Cheng
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Comer
authors.forename: Stacie A
authors.initials: SA
authors.lastname: Dalrymple
authors.forename: Pete
authors.initials: P
authors.lastname: Dunten
authors.forename: JoAnn
authors.initials: J
authors.lastname: Lafargue
authors.forename: Brett
authors.initials: B
authors.lastname: Lovejoy
authors.forename: Jose
authors.initials: J
authors.lastname: Freire-Moar
authors.forename: Julie
authors.initials: J
authors.lastname: Lim
authors.forename: Joel
authors.initials: J
authors.lastname: Mcintosh
authors.forename: Jennifer
authors.initials: J
authors.lastname: Miller
authors.forename: Eva
authors.initials: E
authors.lastname: Papp
authors.forename: Deborah
authors.initials: D
authors.lastname: Reuter
authors.forename: Rick
authors.initials: R
authors.lastname: Roberts
authors.forename: Florentino
authors.initials: F
authors.lastname: Sanpablo
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Kyung
authors.initials: K
authors.lastname: Song
authors.forename: Armando
authors.initials: A
authors.lastname: Villasenor
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Warren
authors.forename: Mary
authors.initials: M
authors.lastname: Welch
authors.forename: Paul
authors.initials: P
authors.lastname: Weller
authors.forename: Phyllis E
authors.initials: PE
authors.lastname: Whiteley
authors.forename: Lu
authors.initials: L
authors.lastname: Zeng
authors.forename: David M
authors.initials: DM
authors.lastname: Goldstein
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D007275:Injections, Intravenous; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D011485:Protein Binding; D020033:Protein Isoforms; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C478623:1-(4-(3-(4-fluorophenyl)-1H-pyrrolo(3,2-b)pyridin-2-yl)pyridin-2-ylamino)propan-2-ol; D004791:Enzyme Inhibitors; D007211:Indoles; D020033:Protein Isoforms; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases