Article pubs.acs.org/jmc
Evolution of a Novel, Orally Bioavailable Series of PI3Kδ Inhibitors from an Inhaled Lead for the Treatment of Respiratory Disease Augustin Amour,† Nick Barton,† Anthony W. J. Cooper,† Graham Inglis,† Craig Jamieson,‡ Christopher N. Luscombe,† Josie Morrell,† Simon Peace,*,† David Perez,†,§ Paul Rowland,† Chris Tame,† Sorif Uddin,† Giovanni Vitulli,† and Natalie Wellaway† †
GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage SG1 2NY, U.K. Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K.
‡
S Supporting Information *
ABSTRACT: A four-step process of high-quality modeling of existing data, deconstruction, identification of replacement cores, and an innovative synthetic regrowth strategy led to the rapid discovery of a novel oral series of PI3Kδ inhibitors with promising selectivity and excellent in vivo characteristics.
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bioavailable compounds such as IPI-14515 and GS-1101 (CAL101, Idelalisib)16 have previously been reported and advanced through clinical studies for oncology indications. Compounds of a similar structural genus have also appeared more recently, for example, UCB-5857 and TGR-1202. All derive from the same chemical series which generally possesses mixed PI3Kδ/γ inhibition, and this lack of selectivity creates difficulties in delineating the role of either isoform in inflammatory disease. More recently still, researchers from Amgen reported potent, selective, and orally bioavailable PI3Kδ inhibitors for the treatment of inflammatory disorders (e.g., AM-8508, 2),17 and researchers from Novatis have progressed CDZ-173 into Phase III trials for the treatment of activated PI3K delta syndrome. Taken together, these events highlight the significant and continuing level of interest associated with this promising therapeutic target. In the current study, we disclose our early efforts toward the discovery of a series of PI3Kδ-selective, orally bioavailable compounds exemplified by the dihydroisobenzofuran derivative 3 (Figure 1) derived from our existing inhaled asset 1 as a potential therapy for respiratory disorders. The aim of the study was to discover an alternative core with reduced clearance and increased bioavailability while retaining the potential to deliver the class-leading levels of selectivity demonstrated by compounds such as 1.
INTRODUCTION The phosphoinositide-3-kinases (PI3Ks) are a family of lipid kinases that are implicated in the development of a range of diseases, including respiratory inflammation.1,2 They comprise three classes based on structure, mode of regulation, and phospholipid substrate. The class I targets have been extensively investigated due to their role in various cancers and inflammatory disease,3 with their biochemical role mediating the phosphorylation of phosphatidylinositol (4,5)diphosphate (PtdIns(4,5)P2) to produce phosphatidylinositol (3,4,5)-triphosphate (PtdIns(3,4,5)P3).4 A number of studies have highlighted the correlation between PI3K-mediated PIP3 production and T cell cytokine release,5 mast cell degranulation,6 neutrophil chemotaxis,7 and the production of reactive oxygen species.8 These cell behaviors have been implicated in the development of respiratory inflammation and a range of cancers. Of the known isoforms, PI3Kδ is found to be predominantly expressed in leucocytes, suggesting it is a promising target for the treatment of asthma,9 chronic obstructive pulmonary disease (COPD),10 and autoimmune disorders.11 From a drug discovery perspective, selectivity among the isoforms is an important consideration. Both PI3Kδ and γ knockout mice are viable and display some impairments of immune cell functions;12,13 however, PI3Kα and β knockouts have been shown to be embryonically lethal.11 We recently reported the discovery of an inhaled clinical candidate, GSK2292767 (1, Figure 1), as a potent and selective PI3Kδ inhibitor with promising in vivo properties as a potential therapy for respiratory indications.14 This compound is structurally related to GSK2269557, also an inhaled therapy and currently in Phase II trials for COPD and asthma. Orally © 2016 American Chemical Society
Received: June 1, 2016 Published: July 18, 2016 7239
DOI: 10.1021/acs.jmedchem.6b00799 J. Med. Chem. 2016, 59, 7239−7251
Journal of Medicinal Chemistry
Article
Figure 1. Structures of 1, 2, and 3.
Figure 2. (a) PLS loadings plot demonstrating groups of coefficients. (b) PLS coefficient plot indicating magnitude, direction, and 95% confidence interval of the mean. Variables of interest: Var 5−8 (ACD Laboratories v11.logd at pH 2, 5.5, 6.5, and 7.4) and Var 9 (cLogP 481); Var 11 (positive ionizable center count) and Var 12 (total charge); Var 23 (estate.amideNH-sum), Var 24 (estate.amideNH-av), and Var 25 (estate.amideOtoNHav). Note: Var 2 is PI3K delta potency.
Figure 3. Design strategy for oral series. The calculated potency is derived via the rearranged BEI calculation (cPI3Kδ pIC50 = 320 × (BEI/1000)).
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the aromatic ring count18 but primarily by contemporaneous literature reports that implicated the indazole group19 as a target for time-dependent P450 inhibition. The general design strategy involved tuning of topological polar surface area (TPSA)20 (
