title: Synthesis and evaluation of a series of 4-azaindole-containing p21-activated kinase-1 inhibitors.
abstract: A series of 4-azaindole-containing p21-activated kinase-1 (PAK1) inhibitors was prepared with the goal of improving physicochemical properties relative to an indole starting point. Indole 1 represented an attractive, non-basic scaffold with good PAK1 affinity and cellular potency but was compromised by high lipophilicity (clogD=4.4). Azaindole 5 was designed as an indole surrogate with the goal of lowering logD and resulted in equipotent PAK1 inhibition with a 2-fold improvement in cellular potency over 1. Structure-activity relationship studies around 5 identified additional 4-azaindole analogs with superior PAK1 biochemical activity (Ki <10nM) and up to 24-fold selectivity for group I over group II PAKs. Compounds from this series showed enhanced permeability, improved aqueous solubility, and lower plasma protein binding over indole 1. The improvement in physicochemical properties translated to a 20-fold decrease in unbound clearance in mouse PK studies for azaindole 5 relative to indole 1.
authors.affiliation: Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: wendyle@gene.com.
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.affiliation: Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Crawford
authors.affiliation: Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Aliagas
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Lesley J
authors.initials: LJ
authors.lastname: Murray
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Tay
authors.affiliation: Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.affiliation: Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Heise
authors.affiliation: Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Hank
authors.initials: H
authors.lastname: La
authors.affiliation: Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Mathieu
authors.affiliation: Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Mintzer
authors.affiliation: Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Sreemathy
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Lionel
authors.initials: L
authors.lastname: Rouge
authors.affiliation: Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C522780:4-azaindole; D007211:Indoles; D047428:Protein Kinase Inhibitors; C515903:PAK1 protein, human; D054462:p21-Activated Kinases
keywords: 4-Azaindole; Aminopyrazole; Diaminopyrimidine; Kinase; PAK1