Theoretical and experimental design of atypical kinase inhibitors: application to p38 MAP kinase.
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.
McClure
Kim F
KF
Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, USA. kim.f.mcclure@pfizer.com
Abramov
Yuriy A
YA
Laird
Ellen R
ER
Barberia
John T
JT
Cai
Weiling
W
Carty
Thomas J
TJ
Cortina
Santo R
SR
Danley
Dennis E
DE
Dipesa
Alan J
AJ
Donahue
Kathleen M
KM
Dombroski
Mark A
MA
Elliott
Nancy C
NC
Gabel
Christopher A
CA
Han
Seungil
S
Hynes
Thomas R
TR
Lemotte
Peter K
PK
Mansour
Mahmoud N
MN
Marr
Eric S
ES
Letavic
Michael A
MA
Pandit
Jayvardhan
J
Ripin
David B
DB
Sweeney
Francis J
FJ
Tan
Douglas
D
Tao
Yong
Y
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*
D001562:Benzimidazoles; D011725:Pyridines; D014230:Triazoles; C014353:benzimidazolone; D048051:p38 Mitogen-Activated Protein Kinases