title: Theoretical and experimental design of atypical kinase inhibitors: application to p38 MAP kinase.
abstract: Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38alpha. The computed descriptors for the hydrophobic and pi-pi interaction capacities were the most useful in ranking potency.
authors.affiliation: Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, USA. kim.f.mcclure@pfizer.com
authors.forename: Kim F
authors.initials: KF
authors.lastname: McClure
authors.forename: Yuriy A
authors.initials: YA
authors.lastname: Abramov
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Laird
authors.forename: John T
authors.initials: JT
authors.lastname: Barberia
authors.forename: Weiling
authors.initials: W
authors.lastname: Cai
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Carty
authors.forename: Santo R
authors.initials: SR
authors.lastname: Cortina
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Danley
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Dipesa
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Donahue
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dombroski
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Elliott
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Gabel
authors.forename: Seungil
authors.initials: S
authors.lastname: Han
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hynes
authors.forename: Peter K
authors.initials: PK
authors.lastname: Lemotte
authors.forename: Mahmoud N
authors.initials: MN
authors.lastname: Mansour
authors.forename: Eric S
authors.initials: ES
authors.lastname: Marr
authors.forename: Michael A
authors.initials: MA
authors.lastname: Letavic
authors.forename: Jayvardhan
authors.initials: J
authors.lastname: Pandit
authors.forename: David B
authors.initials: DB
authors.lastname: Ripin
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Sweeney
authors.forename: Douglas
authors.initials: D
authors.lastname: Tan
authors.forename: Yong
authors.initials: Y
authors.lastname: Tao
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D001562:Benzimidazoles; D011725:Pyridines; D014230:Triazoles; C014353:benzimidazolone; D048051:p38 Mitogen-Activated Protein Kinases