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 collageninduced arthritis model, and a 7 day rat in vivo tolerability study culminated in the selection of compound 22b (AC710) as a preclinical development candidate. KEYWORDS: platelet-derived growth factor receptor (PDGFR)-family kinases, feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3), colony-stimulating factor-1 receptor (CSF1R) inhibitor, acute myeloid leukemia (AML), cancer bone metastasis, inflammatory arthritis, AC710 R eceptor tyrosine kinases (RTKs) are a subfamily of protein kinases that critically regulate the processes of normal cell signaling and many pathological conditions. 1 A class of RTKs known as the platelet-derived growth factor receptor (PDGFR) family, 2,3 which includes colony-stimulating factor-1 receptor (CSF1R, also known as FMS), feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3), stem cell factor receptor (KIT), and PDGFR α and β, has been implicated in various proliferative and inflammatory diseases. 4 We were particularly interested in two members of this family of kinases. Activating internal tandem duplication (ITD) mutations in FLT3 are detected in approximately 30% of acute myeloid leukemia (AML) patients and are associated with poor prognosis. 5 AC220 (1, quizartinib) (Figure 1), a potent FLT3 inhibitor from this laboratory, 6 has demonstrated convincing clinical activity in FLT3-ITD+ AML patients. 7 CSF1R is the exclusive receptor for the macrophage colonystimulating factor (M-CSF or CSF-1). 8 Activation of CSF1R leads to the proliferation, survival, motility, and differentiation of cells of the monocyte/macrophage lineage and hence plays a role in normal tissue development and immune defense. 9,10 Activation of CSF1R also leads to the proliferation and differentiation of osteoclast precursors and therefore mediates the process of bone resorption. 11 It has been shown that M-CSF is one of several cytokines implicated in the recruitment of tumor-associated macrophages (TAMs) that contribute to tumor angiogenesis and tumor progression to metastasis. 12 More recently, the preclinical CSF1R inhibitor GW2580 (2) (Figure 1) inhibited tumor metastasis and angiogenesis in mouse tumor xenograft experiments. 13 JNJ-28312141 (3), a dual inhibitor of CSF1R and FLT3, also demonstrated suppression of solid tumor growth and preservation of bone in preclinical models. 14 CSF1R is also implicated in inflammatory arthritis, as M-CSF, together with RANK ligand, is required for osteoclastogenesis. 15 Elevated M-CFS signaling leads to increased osteoclast activity and bone loss attending arthritis, 16 a...

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“…The pyrazinone building block 1c 7a and 7 were thereafter successfully coupled, following the optimized protocol, to give the product in an excellent yield of 84 % (as a mixture of benzyl and methyl esters; 12a , b ; Scheme ). Methyl ester 12b was formed due to the presence of trace amounts of methanol in the solvent (DME).…”

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