J. Med. Chem. 2009, 52, 7901–7905 7901 DOI: 10.1021/jm900807w
Rapid Generation of a High Quality Lead for Transforming Growth Factor-β (TGF-β) Type I Receptor (ALK5)†,‡ Debreczeni, Richard A. Norman, Frederick W. Goldberg,* Richard A. Ward,* Steven J. Powell, Judit E. Nicola J. Roberts, Allan P. Dishington, Helen J. Gingell, Kate F. Wickson, and Andrew L. Roberts AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K. Received June 4, 2009
A novel class of 4-pyridinoxy-2-anilinopyridine-based TGF-β type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors is reported. The binding mode of this scaffold was successfully predicted by analyzing possible docked binding modes of literature inhibitors and novel synthetic ideas. Compounds such as 19 are potent ALK5 inhibitors with good physicochemical and pharmacokinetic properties and thus represent high quality leads for further optimization.
† We acknowledge the 100th anniversary of the Division of Medicinal Chemistry of the American Chemical Society and are very pleased to be able to contribute to the Centennial Issue of the Journal of Medicinal Chemistry. ‡ Crystal structures of ALK5 in complex with compounds 1 and 19 have been deposited in the Protein Data Bank (PDB accession codes 2WOT and 2WOU, respectively). *To whom correspondence should be addressed. For F.W.G.: phone, þ44(0)1625 519064; fax, ; E-mail Frederick.Goldberg@AstraZeneca. com. For R.A.W.: phone, þ44(0)1625 519045; fax, ; E-mail Richard.A.
[email protected]. a Abbreviations: ALK, activin-like kinase; TGFβ(R), transforming growth factor-β (receptor); DMA, dimethylacetamide; DMF, N,Ndimethylformamide; DMSO, dimethylsulfoxide; SAR, structure-activity relationship.
ALK5 inhibitors from the literature4-14 were modeled using protein-ligand docking software along with manual ligand overlaying. A published ALK5 structure that had a pyrrolopyrazole-based ALK5 inhibitor bound (1RW8) was used for the docking studies.12 The inhibitor binding modes showed some conserved interactions that were consistent across a number of chemical series, in particular a hydrogen bond acceptor to the kinase hinge region (His-283 in ALK5) that is characteristic of the majority of ATP-competitive kinase inhibitors. Interestingly, there was also a hydrogen bond acceptor, usually from a pyridyl (or bipyridyl) group in the inhibitor, which can make a water-mediated hydrogen bond to the protein. This water molecule was observed in the “selectivity pocket”15 of the 1RW8 crystal structure and maintained in the docking calculations due to its likely essential involvement in the observed binding mode. Including this water molecule in the docking studies increased the consistency of the docked poses in a number of inhibitors, suggesting this interaction might be important. We therefore designed and synthesized a number of compounds that would exploit these two key interaction points but which offered scope for further optimization. On the basis of these modeled binding modes, the published inhibitors were manually fragmented into their respective hinge, selectivity pocket, and solvent channel binding regions. Additional hinge region fragments were added from in-house kinase inhibitor structures. The fragments were then hybridized together in different combinations, with all generated compounds containing a hinge region and selectivity pocket group and in some cases a solvent channel group. All generated ideas were docked and suitable structures were then prioritized by synthetic tractability and novelty. This process ultimately resulted in the identification of novel compound 1 (Figure 1), which possesses a bipyridyl group that can access the selectivity pocket and make the aforementioned water-mediated hydrogen bond to the protein. This compound was also predicted to form a key interaction to the hinge with the 2-amino-4-oxo pyridyl (ring 3) and place the trimethoxyaniline fragment (ring 4) into the solvent channel of the kinase binding pocket. Compound 1 had excellent enzyme and cell potency (Table 1) but poor oral bioavailability (rat F = 4%). The
r 2009 American Chemical Society
Published on Web 09/08/2009
Introduction The transforming growth factor family of ligands, including transforming growth factor-β TGFβ,a activins, inhibins, nodal, and bone morphogenic proteins play a key role in controlling cellular functions such as differentiation, migration, proliferation, adhesion, and development.1 This family of ligands signals through heteromeric complexes of type I (e.g., ALK5) and type II serine/threonine kinase (e.g., TGFβRII) receptors. Seven type I receptors have been identified (ALK1 through ALK7) in mammals; signaling specificity is determined by the ligand/receptor complex and the cellular context. Inhibitors of TGFβ signaling may have therapeutic potential in targeting both fibrosis and cancer. While TGFβ can act as a tumor suppressor as well as a tumor promoter, it has been established that levels of TGFβ ligand and its signaling axis are elevated in a wide range of tumor types including breast, colon, gastric, lung, hepatocellular, and pancreatic.2 There is mounting evidence that TGFβ levels within the tumor and local environment correlate to a more aggressive metastatic phenotype, increased angiogenesis, and tumor progression manifested by effects on tumor cells, endothelial cells, and infiltrating cells.3 Hit Identification The ALK5 literature was reviewed to generate ideas for a novel chemical start point. The likely binding modes of known
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ALK5 enzyme assay used a His-tagged fragment (residues 162-503) of the human enzyme, and the cellular assay was a nuclear translocation assay of a GFP/Smad2 fusion reported in MDA-MB-468 cells (see Supporting Information for further details). This compound had acceptable aqueous solubility (52 μM in pH 7.4 phosphate buffer) and in vivo clearance (20 mL/min/kg), so our hypothesis was that the observed low bioavailability was due to poor absorption and/ or high efflux. Although the lipophilicity of 1 as an initial hit was acceptable (logD7.4 = 3.2), it was felt that identifying a smaller analogue while retaining potency (i.e., improving
Goldberg et al.
ligand efficiency)16 would improve our chances of ultimately developing a compound that would have improved absorption and therefore efficacy in vivo.17 Identifying which parts of the scaffold were important for potency therefore became a priority, and again X-ray crystallography was used to help prioritize our efforts. A ligand bound ALK5 crystal structure was generated in-house for 1 (Figure 2A). The observed binding mode corresponded to that predicted by modeling studies and gave us confidence as to how other parts of the active site could be explored from this template. The importance of the nitrogens on the bipyridyl motif was assessed by systematically removing them. Although “ring 2” (Figure 1) appeared to be very important to the binding of the molecule (through the conserved water molecule), it was less clear whether or not the interaction of the “ring 1” pyridine with Lys-232 was required for potency. Further ideas were also generated to probe other regions of the active site, particularly the solvent channel and ribose pocket, as the aniline was predicted to be able to interact with both regions. Chemistry
Figure 1. Predicted binding mode of 1 overlaid with the modeled binding mode of 2, an example from a Kirin patent13 (A). Schematic view of 1 with key areas of the active site highlighted in (B) and the structure of the Kirin compound 2 (C).
The initial hit 1 was synthesized from phenol 313 by basemediated addition to 2,4-dichloropyridine and subsequent Buchwald-Hartwig amination18 with 3,4,5-trimethoxyaniline (Scheme 1). For compounds where the required phenol was difficult to synthesize, an alternative route was also developed via iodo intermediate 4. Negishi coupling19-21 of 4 with 2-pyridylzinc bromide and subsequent Buchwald-Hartwig amination as before afforded the desired compound 5. The Negishi coupling is our preferred method to synthesize bipyridyls due to the known instability of 2-pyridyl boronic acids22 and the toxicity of the equivalent stannanes. In some cases, the base-mediated addition of the phenol group with 2,4-dichloropyridine did not yield the desired product, so to expand the range of phenols that could be used, Ullmann coupling23 with 2-chloro-4-iodo-chloropyridine or base-mediated additions to 2-chloro-4-fluoropyridine were also utilized (Scheme 2). This latter approach has the advantage that the order of the steps can be easily reversed to allow flexible assembly of the target molecules and therefore rapid optimization.
Figure 2. ALK5 ligand bound crystal structures of (A) the initial hit 1 and (B) the lead compound 19. PDB Accession Codes are 2WOT and 2WOU, respectively.
Brief Article
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Table 1
compd
R1
R2
R3
R4
enzyme IC50, nMa
LEb
cell IC50, nMa
logD7.4c
rat, F% (AUC)d
1 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
2-pyridyl 2-pyridyl Me H H Me 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl Me
Me Me Me H Me H Me Me Me Me Me Me Me Me Me Me
Me H H H H H Me Me Me Me Me Me Me Me Me H
3,4,5-trimethoxy 3,4,5-trimethoxy 3,4,5-trimethoxy 3,4,5-trimethoxy 3,4,5-trimethoxy 3,4,5-trimethoxy 2-OMe 2-morpholino 3-OMe 3-morpholino 4-OMe 4-morpholino 4-SO2NH2 4-CONMe2 4-F 4-SO2NH2
44 (27-73) 13 (11-14) 35 (19-62) 227 (107-482) 108 (40-294) 107 (61-187) 7 (2-21) 739 (615-887) 4 (4-4) 6 (5-7) 30 (22-40) 109 (79-150) 21 (15-30) 12 (12-13) 129 (88-188) 72 (63-82)
0.22 0.24 0.27 0.26 0.26 0.26 0.27 0.18 0.28 0.24 0.25 0.2 0.24 0.24 0.24 0.27
55 (39-77) 20 (17-25) 21 (17-26) >5800 282 (221-361) 628 (291-1355) 114 (86-150) >3000 32 (17-60) 62 (56-69) 35 (22-54) 146 (85-251) 27 (23-31) 31 (27-36) 63 (33-120) 22 (19-25)
3.2 3.4 3 2.7 3.2 3.2 3.4 3.1 nd 3.3 3.5 2.6 2.3 3.4 3.2 2.5
4 (0.15) 21 (0.34)
20 (0.47)
75 (4.95)
a
IC50 data are the geometric mean of at least 2 independent values (66% confidence limits are given in parentheses, as calculated from the standard error of the mean). b Enzyme pIC50/heavy atom count. To convert to ΔG-based ligand efficiencies as used by, e.g., Astex, multiply by 1.37. c The partition coefficient between pH7.4 sodium phosphate buffer and octanol. d Oral bioavailability (with oral AUC in μM.h in parentheses) observed when dosing compound as a 5 μmol/kg solution to male Han Wistar rats. nd = not determined.
Scheme 1a
Scheme 2a
a Reagents and conditions: (i) ROH, Cs2CO3, CuI, DMA, 25-77%; (ii) ArNH2, Pd(OAc)2, Xantphos, Cs2CO3, 1,4-dioxane or DMA, 38-75%; (iii) ROH, K2CO3, DMF, 50-82%.
a
Reagents and conditions: (i) NaH, DMF, 2,4-dichloropyridine, 51%; (ii) Pd(OAc)2, Xantphos, Cs2CO3, 1,4-dioxane, 3,4,5-trimethoxyaniline, 38%; (iii) NaH, DMF, 2,4-dichloropyridine, 100%; (iv) 2pyridylzinc bromide, Pd(PPh3)4, THF/DMA, 56%; (v) Pd(OAc)2, Xantphos, Cs2CO3, 1,4-dioxane, 3,4,5-trimethoxyaniline, 14%.
Results and Discussion Guided by the X-ray crystallography results, we examined the SAR of the 4-pyridinoxy-2-anilinopyridine scaffold with the goal of improving the PK properties and cellular potency of the original hit compound 1. To assess PK properties, we used in vivo rat PK as we did not have a convincing correlation between in vitro hepatocyte data and in vivo clearance. Variation of the phenol group (Table 1) focused on optimizing R2 and R3 while aiming to replace the 2-pyridyl at R1 with a smaller equipotent group to optimize ligand efficiency (defined in this article as pIC50/heavy atom count) and predicted physicochemical properties. Thus removal of the
methyl at R3 improved the cellular potency (cf. 1 and 5). Even more importantly, the pyridyl at R1 could be replaced with a methyl group (cf. 5 and 6) while maintaining potency and thus improving ligand efficiency. Both methyls of 6 were important for potency, as evidenced by the fact that 7, 8, and 9 are all less potent than 6. The 2,6-dimethylpyridyl group was therefore identified as the most attractive selectivity pocket group due to its potency and ligand efficiency (and therefore favorable predicted physicochemical properties). Simultaneously, we examined the SAR of the aniline group (Table 1). Thus, ortho substitution by a methoxy group as in 10 was well tolerated, although the larger morpholine 11 did slightly reduce potency. Both methoxy and morpholine groups gave excellent levels of potency in the meta and para positions (12-15) along with small and large electron withdrawing groups (e.g., 16-18 shown for para substitution). As a wide range of substitution patterns was tolerated on the aniline group, varying this group was predicted to be a successful approach to optimize DMPK and physical properties. With the preliminary SAR established, we were able to rapidly identify lead compounds with improved pharmacokinetic profiles over the initial hit 1. Thus replacement of the bipyridyl phenol with the smaller, more ligand efficient
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2,6-dimethylpyridyl group gave a modest improvement in rat bioavailability and oral exposure (from F = 4%, AUC = 0.29 μM 3 h for 1 to F = 21%, AUC = 0.67 μM 3 h for 6) as did replacement of the 3,4,5-trimethoxyaniline with groups such as 4-aminobenzenesulfonamide (F = 20%, AUC = 0.47 μM 3 h for 16), although neither of these changes reduced rat IV clearance. Combining these changes to give 19, however, gave a compound with high bioavailability and oral exposure (F = 75%, AUC = 4.95 μM 3 h) with low clearance (12 mL/min/kg). This compound also had excellent cell potency (22 nM), low molecular weight (370), and suitable lipophilicity (logD7.4 = 2.5) to make it a novel, high quality lead compound for further optimization. The crystal structure of this compound was solved to assess further ways in which this series could be modified (Figure 2B). The binding mode of 19 was consistent with 1 but with an additional interaction between the NH2 of the sulfonamide group and the carboxyl group of Asp-290. The general kinase selectivity of 19 was also assessed by submission to a panel of 80 representative kinases24 at Dundee University; only five kinases showed >50% inhibition at 1 μM, of which only two showed inhibition of >80%. In conclusion, we have developed a novel series of ALK5 inhibitors based upon the 4-pyridinoxy-2-anilinopyridine scaffold. The binding mode of the initial hit compound was successfully predicted by docking studies prior to synthesis and then later confirmed by X-ray crystallography. Optimization of this scaffold focused on improving ligand efficiency and controlling lipophilicity in order to improve pharmacokinetic properties. Combining the optimal structural changes to each position on the central core gave 19, which has excellent cell potency and suitable physicochemical and pharmacokinetic properties for further optimization. Compound 19 also demonstrates an excellent selectivity profile across a panel of 80 kinases. Experimental Section General. All MS data were obtained using a Waters LCMS using electrospray. 1H NMR spectra were collected on a 300 MHz Bruker spectrometer unless otherwise stated. Column chromatography was performed using an Isco Combi Flash Companion system. Preparative HPLC was performed on C18 reversed-phase silica on a Waters preparative reversed-phase column (5 μm silica, 19 mm 100 mm) or on a Phenomenex preparative reversed-phase column (5 μm silica, 21.1 100 mm) using decreasingly polar mixtures of water (containing 1% formic acid or 1% aq NH4OH) and MeCN. The purity of all test compounds was >95% except for 11, where the measured purity was 85%. Purity was ascertained from AUC (UV detection from 220 to 300 nm) by analytical HPLC using a Waters LCMS, on a Phenomenex reversed-phase column (5 μm silica, 2 mm 50 mm), eluting from 95:5 A:C to 95:5 B:C over 4 min, and then held at 95:5 B:C for 0.5 min before returning to 95:5 A: C for 0.5 min, where eluents A, B, and C are A = water, B = MeCN, C = 50:50 MeCN:1% aq NH4OH. Synthesis of Representative Example: 4-({4-[(2,6-Dimethylpyridin-3-yl)oxy]pyridin-2-yl}amino)benzenesulfonamide (19). Solutions of 2,6-dimethylpyridin-3-ol (0.209 g) in DMF (2 mL) and 2,4-dichloropyridine (0.3 g) in DMF (3 mL) were added to a suspension of NaH (60% dispersion in mineral oil, 0.136 g) in DMF (5 mL). After stirring for 20 min at room temperature, the mixture was heated at 100 °C for 2 h. The mixture was taken up in ethyl acetate and water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by flash column chromatography, eluting with 0-70% ethyl acetate/iso-hexane,
Goldberg et al.
gave 3-(2-chloropyridin-4-yl)oxy-2,6-dimethyl-pyridine (0.212 g, 53%) as a yellow solid. 1H NMR (DMSO): 2.28 (3H, s), 2.48 (3H, s), 6.90 (1H, dd), 6.99 (1H, d), 7.22 (1H, d), 7.52 (1H, d), 8.29 (1H, d); m/z: MHþ 235.7. A mixture of 3-(2-chloropyridin-4-yl)oxy2,6-dimethyl-pyridine (0.2 g, 0.85 mmol), sulfanilamide (0.191 g), Cs2CO3 (0.417 g), Pd(OAc)2 (0.013 g), Xantphos (49 mg), and DMA (2 mL) was heated at 150 °C for 10 min in a microwave. After cooling, the crude product was semipurified by ion exchange chromatography, eluting with 7 M NH3/methanol. Further purification by preparative HPLC using decreasingly polar mixtures of water (containing 0.1% TFA) and acetonitrile as eluent gave 19 (0.17 g, 54%) as a solid. 1H NMR (DMSO): 2.30 (3H, s), 2.49 (3H, s), 6.13 (1H, d), 6.52-6.56 (1H, m), 7.10 (2H, s), 7.23 (1H, d), 7.50 (1H, d), 7.68 (2H, d), 7.79 (2H, d), 8.14 (1H, d), 9.38 (1H, s); m/z: MHþ 371.0.
Acknowledgment. We thank Jason Kettle, Ray Finlay, Brian Law, Nabil Asaad, and Philip Jewsbury for their advice and support. Our heartfelt thanks are also given to Robert Cheung, who performed the insect cell culture and who is sorely missed by all. Supporting Information Available: General experimental procedure, procedures for preparation of all final compounds and their precursors and NMR data and purity statements, enzymatic and cell-based assay procedures, procedures for protein expression and X-ray crystallography, computational chemistry techniques. This material is available free of charge via the Internet at http://pubs.acs.org.
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