title: Discovery of pyrroloaminopyrazoles as novel PAK 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.
authors.affiliation: Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States. alexguo01@gmail.com
authors.forename: Chuangxing
authors.initials: C
authors.lastname: Guo
authors.forename: Indrawan
authors.initials: I
authors.lastname: McAlpine
authors.forename: Junhu
authors.initials: J
authors.lastname: Zhang
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Knighton
authors.forename: Susan
authors.initials: S
authors.lastname: Kephart
authors.forename: M Catherine
authors.initials: MC
authors.lastname: Johnson
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.forename: Djamal
authors.initials: D
authors.lastname: Bouzida
authors.forename: Anle
authors.initials: A
authors.lastname: Yang
authors.forename: Liming
authors.initials: L
authors.lastname: Dong
authors.forename: Joseph
authors.initials: J
authors.lastname: Marakovits
authors.forename: Jayashree
authors.initials: J
authors.lastname: Tikhe
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Guo
authors.forename: Robert
authors.initials: R
authors.lastname: Kania
authors.forename: Martin P
authors.initials: MP
authors.lastname: Edwards
authors.forename: Eugenia
authors.initials: E
authors.lastname: Kraynov
authors.forename: James
authors.initials: J
authors.lastname: Christensen
authors.forename: Joseph
authors.initials: J
authors.lastname: Piraino
authors.forename: Joseph
authors.initials: J
authors.lastname: Lee
authors.forename: Eleanor
authors.initials: E
authors.lastname: Dagostino
authors.forename: Christine
authors.initials: C
authors.lastname: Del-Carmen
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Deng
authors.forename: Tod
authors.initials: T
authors.lastname: Smeal
authors.forename: Brion W
authors.initials: BW
authors.lastname: Murray
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002219:Carbamates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004285:Dogs; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010539:Permeability; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D002219:Carbamates; D011720:Pyrazoles; D011758:Pyrroles; D054462:p21-Activated Kinases