Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design

Abstract

ABSTRACT:In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC 50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC 50 = 2 nM), PK properties, and a robust PK/PD relationship. KEYWORDS: Autotaxin, tool molecule, osteoarthritis, LPA O steoarthritis (OA) is a highly prevalent disease affecting many adults including more than one out of three individuals aged 65 or older in the United States.1 In addition to significant accompanying pain, OA frequently leads to pronounced disability resulting in the loss of work, hospitalization, and joint replacement procedures.2 Current first-line pharmacological treatment options for OA focus on reducing inflammation and the associated pain. Nonsteroidal antiinflammatory drugs (NSAIDS) and selective COX-2 inhibitors are among the most prescribed medications for OA pain but unfortunately are also frequently accompanied by gastrointestinal, renal, and CV side effects, limiting their use. 3 Recently, the role of lyosophosphatidic acid (LPA) in certain inflammatory conditions has been studied. 4 LPA exists as a number of molecular species that have variable saturated and unsaturated fatty acid chains.5 Signaling of LPA through six GPCRs (LPA Receptors 1−6) has been shown to lead to the upregulation of inflammatory cytokines and matrix metalloproteinases, which contribute to the pathogenesis of OA. 6LPA signaling has also been associated with many other pathologies, such as pulmonary fibrosis and cancer. In vivo, the enzyme autotaxin (ATX), with lyosophosopholipase D activity, is the primary source of extracellular LPA, which results from the cleavage of choline from lysophosphatidylcholine (LPC) (Figure 1). LPA is also produced through action of secreted phospholipases A2 (sPLA2) on phosphatidic acid (PA), although this is believed to be a minor route of extracellular LPA production in vivo. 8,9 Autotaxin is an extracellular, 125 kDa protein that was originally characterized in 1993 by Stracke et al. as a motility stimulating protein. 10 In 2002, Umezu-Goto and co-workers demonstrated that ATX was the same protein as a known lysophopholipase D enzyme, which catalyzed the conversion of LPC to LPA.11 Autotaxin is a multidomain protein with two Nterminal somatomedin B-like domains, a centrally located phosphodiesterase domain, and a catalytically inactive nuclease-like domain on the C-terminal region. It is expressed in four main isoforms (ATXα−δ) with largely unknown differential functionality in vivo.7 The catalytic domain of ATX comprises two zinc ions coordinated with histidine and aspartic acid residues with a threonine alcohol serving as the nucleophile. A large hydro...

Design, synthesis, and biological evaluation of 2,4-dihydropyrano[2,3-c]pyrazole derivatives as autotaxin inhibitors

“…Interestingly, especially the hydrogen bond with W276 and π-π A C C E P T E D M A N U S C R I P T interaction with F275 seems to be crucial in the inhibitor binding. W276 hydrogen bond exist in 5L0K (Jones et al, 2016) (PF8380), 5L0B (Jones et al, 2016), 5L0E (Jones et al, 2016), 4ZGA (Stein et al, 2015), 4ZG6 (Stein et al, 2015), 3WAV (Kawaguchi et al, 2013), 3WAW (Kawaguchi et al, 2013), 3WAX (Kawaguchi et al, 2013) and 3WAY (Kawaguchi et al, 2013) structures, whereas π-π interaction with F275 can be observed in 5L0B (Jones et al, 2016), 5L0E (Jones et al, 2016), 4ZG7 (Stein et al, 2015), 4ZG9 (Stein et al, 2015), 4ZGA (Stein et al, 2015), 3WAW (Kawaguchi et al, 2013) and 3WAX (Kawaguchi et al, 2013) structures.…”

Pharmacological Characterization of a Potent Inhibitor of Autotaxin in Animal Models of Inflammatory Bowel Disease and Multiple Sclerosis

“…We recently described the identification of compound-1 (Fig. 1A) as an orally available small molecule that inhibits autotaxin with an IC 50 of ∼2 nM in an ex vivo human whole blood assay and does not inhibit related proteins ENPP1 and ENPP7 (Beauchamp et al, 2015;Jones et al, 2016). Administration of this compound in rats results in a dose-and time-dependent inhibition of plasma LPA levels.…”

Identifying Novel ATX Inhibitors via Combinatory Virtual Screening Using Crystallography-Derived Pharmacophore Modelling, Docking Study, and QSAR Analysis

“…Since the ATX-LPA signaling axis has been involved in a number of pathologies, including cancer [3][4][5][6][7], pain [8][9][10], and cholestatic pruritus [11,12], as well as fibrotic [13][14][15], inflammatory [16][17][18] and cardiovascular diseases [19], it attracts high interest in the drug discovery industry.…”

“…Recently, lots of patents and literature reported numerous ATX inhibitors with probable application for the treatment of diverse pathologies [10,14,[20][21][22]. For example, Nicolas Desroy identified a first-in-class ATX inhibitor, GLPG1690, which has been undergoing clinical evaluation for the treatment of idiopathic pulmonary fibrosis [14].…”

“…For example, Nicolas Desroy identified a first-in-class ATX inhibitor, GLPG1690, which has been undergoing clinical evaluation for the treatment of idiopathic pulmonary fibrosis [14]. An aminopyrimidine series with an ATX IC 50 of 500 nM were developed by Spencer B. Jones, for the treatment of osteoarthritis pain [10]. The imidazo [1,2-a]pyridine series of ATX inhibitors were identified by the Nicolas Desroy and Bertrand Heckmann group [22].…”