1. Discovery of pyrroloaminopyrazoles as novel PAK inhibitors.
- Author
-
Guo C, McAlpine I, Zhang J, Knighton DD, Kephart S, Johnson MC, Li H, Bouzida D, Yang A, Dong L, Marakovits J, Tikhe J, Richardson P, Guo LC, Kania R, Edwards MP, Kraynov E, Christensen J, Piraino J, Lee J, Dagostino E, Del-Carmen C, Deng YL, Smeal T, and Murray BW
- Subjects
- Administration, Oral, Amides chemical synthesis, Amides pharmacokinetics, Amides pharmacology, Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Carbamates chemistry, Carbamates pharmacokinetics, Carbamates pharmacology, Crystallography, X-Ray, Dogs, Humans, Hydrogen Bonding, Mice, Models, Molecular, Molecular Conformation, Permeability, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Pyrroles pharmacokinetics, Pyrroles pharmacology, Rats, Stereoisomerism, Structure-Activity Relationship, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents chemical synthesis, Pyrazoles chemical synthesis, Pyrroles chemical synthesis, p21-Activated Kinases antagonists & inhibitors
- Abstract
The P21-activated kinases (PAK) are emerging antitumor therapeutic targets. In this paper, we describe the discovery of potent PAK inhibitors guided by structure-based drug design. In addition, the efflux of the pyrrolopyrazole series was effectively reduced by applying multiple medicinal chemistry strategies, leading to a series of PAK inhibitors that are orally active in inhibiting tumor growth in vivo.
- Published
- 2012
- Full Text
- View/download PDF