title: Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases.
abstract: A series of potent, selective platelet-derived growth factor receptor-family kinase inhibitors was optimized starting from a globally selective lead molecule 4 through structural modifications aimed at improving the physiochemical and pharmacokinetic properties, as exemplified by 18b. Further clearance reduction via per-methylation of the α-carbons of a solubilizing piperidine nitrogen resulted in advanced leads 22a and 22b. Results from a mouse tumor xenograft, a collagen-induced arthritis model, and a 7 day rat in vivo tolerability study culminated in the selection of compound 22b (AC710) as a preclinical development candidate.
authors.affiliation: Departments of Medicinal Chemistry, Cell Biology and Pharmacology, Technology Development, and DMPK and Toxicology, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Departments of Medicinal Chemistry, Cell Biology and Pharmacology, Technology Development, and DMPK and Toxicology, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Campbell
authors.affiliation: Departments of Medicinal Chemistry, Cell Biology and Pharmacology, Technology Development, and DMPK and Toxicology, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Holladay
authors.affiliation: Departments of Medicinal Chemistry, Cell Biology and Pharmacology, Technology Development, and DMPK and Toxicology, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Ford Pulido
authors.affiliation: Departments of Medicinal Chemistry, Cell Biology and Pharmacology, Technology Development, and DMPK and Toxicology, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Helen
authors.initials: H
authors.lastname: Hua
authors.affiliation: Departments of Medicinal Chemistry, Cell Biology and Pharmacology, Technology Development, and DMPK and Toxicology, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Dana
authors.initials: D
authors.lastname: Gitnick
authors.affiliation: Departments of Medicinal Chemistry, Cell Biology and Pharmacology, Technology Development, and DMPK and Toxicology, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gardner
authors.affiliation: Departments of Medicinal Chemistry, Cell Biology and Pharmacology, Technology Development, and DMPK and Toxicology, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Joyce
authors.initials: J
authors.lastname: James
authors.affiliation: Departments of Medicinal Chemistry, Cell Biology and Pharmacology, Technology Development, and DMPK and Toxicology, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Mike A
authors.initials: MA
authors.lastname: Breider
authors.affiliation: Departments of Medicinal Chemistry, Cell Biology and Pharmacology, Technology Development, and DMPK and Toxicology, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Brigham
authors.affiliation: Departments of Medicinal Chemistry, Cell Biology and Pharmacology, Technology Development, and DMPK and Toxicology, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Barbara
authors.initials: B
authors.lastname: Belli
authors.affiliation: Departments of Medicinal Chemistry, Cell Biology and Pharmacology, Technology Development, and DMPK and Toxicology, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Armstrong
authors.affiliation: Departments of Medicinal Chemistry, Cell Biology and Pharmacology, Technology Development, and DMPK and Toxicology, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Treiber
keywords: AC710; acute myeloid leukemia (AML); cancer bone metastasis; colony-stimulating factor-1 receptor (CSF1R) inhibitor; feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3); inflammatory arthritis; platelet-derived growth factor receptor (PDGFR)-family kinases