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. 2024 Apr 26;15(5):714–721. doi: 10.1021/acsmedchemlett.4c00102

A Tiny Pocket Packs a Punch: Leveraging Pyridones for the Discovery of CNS-Penetrant Aza-indazole IRAK4 Inhibitors

Philippe N Bolduc †,*, Magnus Pfaffenbach †, Ryan Evans †, Zhili Xin †, Kate L Henry ‡, Fang Gao †, Terry Fang ‡, John Silbereis ‡, Jorge Vera Rebollar ‡, Pei Li §, Jayanth V Chodaparambil ∥, Claire Metrick ∥, Emily A Peterson †,*
PMCID: PMC11089553  PMID: 38746903

Abstract

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We herein report the discovery, synthesis, and evolution of a series of indazoles and azaindazoles as CNS-penetrant IRAK4 inhibitors. Described is the use of structure-based and property-based drug design strategically leveraged to guide the property profile of a key series into a favorable property space while maintaining potency and selectivity. Our rationale that led toward functionalities with potency improvements, CNS-penetration, solubility, and favorable drug-like properties is portrayed. In vivo evaluation of an advanced analogue showed significant, dose-dependent modulation of inflammatory cytokines in a mouse model. In pursuit of incorporating a highly engineered bridged ether that was crucial to metabolic stability in this series, significant synthetic challenges were overcome to enable the preparation of the analogues.

Keywords: IRAK4, Inflammation, Kpuu, Indazole, CNS-penetrant, pyridone

Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) is a serine/threonine kinase operating as a critical node controlling the response of the interleukin receptor family (IL-1, IL18, and IL-33 receptors) as well as the Toll-like receptors (TLR) pathway.1 Dysregulation, specifically abnormal activation of IRAK4 signaling, is associated with an array of disease pathology.2,3 Evidence of the benefits on central nervous system (CNS) inhibition of IRAK4 is emerging as an advantageous strategy to address unmet medical needs.4−7 We therefore pursued the development of CNS-penetrant IRAK4 inhibitors to modulate associated neurological pathologies. Targeting CNS-penetrant ATP-competitive kinase inhibitors is a challenging endeavor owing to the difficulty of reducing the number of H-bond donors to avoid PgP efflux, while also achieving solubility with kinase inhibitors that usually consist of planar aromatic functionality as a mimic of ATP.8−10 Achieving a favorable ratio of unbound brain concentration to unbound plasma concentration (Kpu, u; Kpu, u = (Cb×Fub/Cp×Fup), Cb: measured total drug concentration in brain, Fub: unbound drug fraction in brain, Cp: measured total drug concentration in plasma, Fup: unbound drug fraction in plasma) is critical to achieving a safe therapeutic that does not incur unwanted side effects due to increased exposure in the periphery to achieve the desired concentration in the brain. Additionally, targeting the CNS can lead to a new set of off-target selectivity considerations that are otherwise not observed when the compounds are peripherally restricted.

The medicinal chemistry effort described herein was part of a larger campaign11−13 exploring multiple 5–6 heterocyclic systems and their ability to selectively inhibit IRAK4 kinase function and penetrate the CNS with adequate safety margins.14−16 Previous efforts had been successful in identifying potent, selective, and CNS-penetrant IRAK4 inhibitors such as BIO-7488 (1, Figure 1). However, solubility limited the development of such compounds, leading to unpredictable PK, in vivo compound accumulation, and poor tolerability of the compound. Therefore, the focus of the campaign pivoted toward the design of compounds with decreased lipophilicity and increased Fsp3,17 but with care to maintain a suitable balance of properties to remaining brain penetrant. As such, compounds were evaluated for their solubility, eLogD, and susceptibility to P-glycoporotein efflux (PgP, also known as MDR1) by measuring the efflux ratio (ER) in MDCK-MDR1 cells prior to in vivo cassette Kpu, u experiments in rats, where both the brain–plasma partitioning and the in vivo clearance information were collected. Review of the previously established SAR in our program found that the bicycloether moiety in 1 brought both potency and metabolic stability and was also the major sp3-hybridized element in the compound, which was desirable for solubility.18,19 Additionally, it was found that most structural modifications to the isopropyl ether, such as adding rotatable bonds or simple inclusion of additional heteroatoms (for instance, oxygen, nitrogen, or even fluorine atoms), resulted in a significant increase of MDR1 efflux, and so the isopropyl ether was considered optimal for our series despite the available space in the pocket to grow further.

Figure 1.

Figure 1

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General overview of compound 1.

The overall planarity of the aromatic 5,6-heterocyclic core was required for binding to the pocket, the amide interacts with the hinge Met265, and it was observed that one of the nitrogens located on the core was making a key water-mediated interaction with the protein (Figure 1). Moreover, while a pendant aromatic ring on the amide was also required, as it made a pi-stacking interaction with TYR262, SAR showed this area to be quite accommodating to substitutions. A cocrystal structure of compound 1 was analyzed to help the structure-based design evolution of the compounds; in Figure 2, we highlighted a tent-like bulge located above the pyrazolopyrimidine piece of compound 1. That bulge is an open space gated by Alanine 211, Valine 200, Lysine 213, and the gatekeeper Tyrosine 262. During the campaign, we found that the pyrazolopyrimidine piece could effectively be replaced by an N-alkylated pyridone where we observed a manageable loss in potency, going from 0.6 nM IC50 IRAK4 biochemical potency for compound 1, to an IC50 in the vicinity of 2 nM (approximately a 4× loss) for compounds 2 and 3 which do not have the optimal bridged cycle on the left-hand side. This loss was accompanied by a beneficial reduction in lipophilicity (eLogD of 2.5 for compound 1 vs 1.92 and 1.81, respectively, for compound 2 and 3) and strategically placed us in a position to grow the Fsp3 of the compounds via the N-alkyl handle of the pyridone, allowing us to take advantage of the bulge observed in this location. Solubility was improved for all the compounds made with this new aryl piece (Table 1), and while this strategic lipophilic retreat came at the expense of an increased MDR1 efflux as observed for compounds 2 and 3 (Table 1), we had effectively set the stage to enable sp3 growth in the bulge pocket (Table 2 and 3), which later helped to improve the ER.

Figure 2.

Figure 2

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PDB 8UCC. Co-crystal structure of IRAK4 bound to compound 1. The mesh surface depicts a bulged open space pocket created by Ala211, Val200, Lys213, and Tyr262 that is located above the pyrazolopyrimidine of the ligand.

Table 1. Comparison between Early-Stage Analogue Lead Series Being Evaluated.

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a

Results represent the arithmetic mean of a minimum of two experiments.

b

MDCK–MDR1 human P-gp transfected cell line. Papp(A–B): apparent permeability apical-to-basolateral (10–6 cm/s); ER = B–A/A–B efflux ratio.

c

Kinetic Solubility Assay.

d

Scaled Intrinsic Clearance determined in human liver microsomes and hepatocytes.

Table 2. Pyridone Substitution SAR with Bridge Ether Attached.

graphic file with name ml4c00102_0011.jpg

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a

Results represent the arithmetic mean of a minimum of two experiments.

b

MDCK–MDR1 human P-gp transfected cell line. Papp(A–B): apparent permeability apical-to-basolateral (10–6 cm/s); ER = B–A/A–B efflux ratio.

c

Kinetic Solubility Assay.

d

Scaled Intrinsic Clearance determined in human liver microsomes and hepatocytes.

e

Human whole blood potency corrected for free fraction.

f

Kpu, u = (Cb×Fub/Cp×Fup). Cb: measured total drug concentration in brain, Fub: unbound drug fraction in brain, Cp: measured total drug concentration in plasma, Fup: unbound drug fraction in plasma.

g

In vivo male Sprague Dawley Rat infusion clearance measured during Kpuu procedure (see SI).

Table 3. Pyridone Methyl/Fluoro Cyclopropyl Substitutions SAR on Azaindazole Core.

graphic file with name ml4c00102_0012.jpg

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a

Results represent the arithmetic mean of a minimum of two experiments.

b

MDCK–MDR1 human P-gp transfected cell line. Papp(A–B): apparent permeability apical-to-basolateral (10–6 cm/s); ER = B–A/A–B efflux ratio.

c

Kinetic Solubility Assay.

d

Scaled Intrinsic Clearance determined in human liver microsomes and hepatocytes.

e

Unbound fraction of the test compound.

f

Kpu, u = (Cb×Fub/Cp×Fup). Cb: measured total drug concentration in brain, Fub: unbound drug fraction in brain, Cp: measured total drug concentration in plasma, Fup: unbound drug fraction in plasma.

g

In vivo male Sprague Dawley Rat infusion clearance measured during Kpuu procedure (see SI)

h

Human whole blood potency corrected for free fraction.

An in-silico analysis using an internal model predicted that changing the 5,6-heterocyclic core to an indazole or aza-indazole, as observed, respectively, by compounds 4 and 5 (Table 1) would result in improved ER when compared to their counterparts 2 and 3 (Table 1). Both series previously suffered from very low solubility when the hinge binding amide was combined with our historically preferred aryl handles, such as that shown in 1. Further profiling revealed that compound 5 was more potent and soluble, as well as demonstrated improved metabolic stability when compared to 4. Evaluation of multiple matched pairs (data not shown) revealed that this trend was generally applicable to multiple analogues. As such, the exploration of these two cores was of interest; however, the chemistry to access the optimized bridge THF on the left-hand side of the compounds was not straightforward, and thus a different synthesis route was investigated.

Traditional coupling methods or photoredox technologies were not successful in forging the connection between the tertiary carbon and the nitrogen at the 2-position on the indazole. These methods either suffered from poor yields or provided undesired regioselectivity on the indazole nitrogen. After a substantial effort investigating multiple methods and disconnections, a Cadogan cyclization strategy was devised.20−22 The synthesis started from a phenolic pyridine precursor that was converted to pyridine 12 using triflic anhydride (see Supporting Information for the complete synthesis). The olefin was installed via a Suzuki coupling to yield 13, then the aldehyde was revealed with a Lemieux–Johnson oxidation23 via olefin cleavage which produced 14. This intermediate was used to investigate the Cadogan cyclization. The initial one-pot attempts to convert 14 directly to 16 provided poor cyclization yields in the range of 5%. Ultimately, it was found that performing the reaction in a stepwise manner, by isolating imine 15 first and then performing the Cadogan cyclization, improved the yields substantially. Although the yields were lower than desired, this route allowed the initial in vitro comparative analysis of both indazoles cores (Table 2, Scheme 1).

Scheme 1. Initial Synthetic Route Evaluated to Install Bridge Ether to (Aza)-indazoles Cores.

Scheme 1

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Grafting these bridged cycles to both indazole cores led to significant improvements in biochemical potency of 4- and 8-fold for both the indazole and aza-indazole series, respectively, as exemplified by compounds 6 and 7 (Table 2). It was also notable that this change improved efflux ratios as well as improved in vitro clearance while maintaining the desired solubility compared to compounds 4 and 5 (Table 1). The measured rat brain Kpu, u24 partitioning of 6 and 7 was impressive with values of 1, and further profiling revealed that compound 7 demonstrated superior human whole blood potency to compound 6. While compound 7 was superior in both potency and lower in vitro clearance, the chemistry to access the indazole core of 6 was initially more amenable to scale-up and was used to explore the impact of the pyridone N-alkyl substitutions (Table 2). The N-alkyl exploration led us to the discovery of the cyclopropyl moiety in 8 as a highly potent alternative to the methyl found in analogues 6 and 7. We observed a clear SAR trend favoring cyclopropyl 8, while larger substituents led to diminished potency.

Compound 6 was profiled in an in vivo PK/PD study in a mouse model where one cohort of animals was dosed orally with 0, 10, 30, and 100 mpk of the compound, respectively. The experiment was designed to measure the dose–response modulation of cytokine production following pathway stimulus by intraperitoneal injection (i.p.) delivery of lipopolysaccharide (LPS)25 to mice dosed with compound 6. In addition to exposure data collected, Inhibition of cytokines by 6 was measured in both the plasma and the brain (Figures 3 and 4). Significant dose-dependent reduction of plasma pro-inflammatory cytokines IL-1β, TNFα, MCP-1, KC-GRO, and IL-6 was observed, with a corresponding dose-dependent increase in plasma levels of anti-inflammatory cytokine IL-10. Similar results were obtained in the CNS for all cytokines tested with the exception of IL-10, which remained at or above control levels. While it is unclear whether reduced neuroinflammation with compound 6 is due to inhibition of peripheral or CNS IRAK4, the free brain concentration of compound 6 predicts that exposures would be sufficient to exceed IC80 and inhibit IRAK4 activity in the brains. Additionally, it was known from previous internal experiments that inhibition in the peripheral IP-LPS PD studies mirrored effects observed when LPS was delivered directly to the CNS using intracerebroventricular injection (ICV) dosing.

Figure 3.

Figure 3

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Vehicle (0 mpk) or Compound 6 (10, 30, or 100 mpk) was dosed orally 60 min prior to i.p. LPS. In vivo plasma cytokine levels and free drug concentration are shown at 90 min post-LPS stimulation. Cytokine levels are in white symbols, and drug exposures in plasma are depicted by red symbols. One-way ANOVA was used for cytokine analysis where each group is compared to the group dosed with 0 mpk compound 6 and administered i.p. LPS.

Figure 4.

Figure 4

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Vehicle (0 mpk) or Compound 6 (10, 30, or 100 mpk) was dosed orally 60 min prior to i.p. LPS. In vivo brain cytokine levels and free drug concentration are shown at 90 min post-LPS stimulation. Cytokine levels are in white symbols, and drug exposures in plasma are depicted by red symbols. One-way ANOVA was used for cytokine analysis where each group is compared to the group dosed with 0 mpk compound 6 and administered i.p. LPS.

The excellent in vivo inhibition of cytokines by compound 6 supported the prospect of exploring the more difficult-to-access aza-indazole core analogues, which were expected to provide superior potency and PK.

To improve the yield of the Cadogan cyclization, an array of solvent/phosphine/temperature conditions were evaluated using high-throughput experimentation (Supporting Information). This effort resulted in the use of tricyclohexylphosphine in combination with methanol as the most advantageous conditions, which were used in a successful scale-up campaign of the intermediate 19 that would enable us to perform our desired SAR investigation (Scheme 2). Using intermediate 19, we were set to explore the effect of various pyridones attached to the hinge-binding core which were synthesized via a method developed in our lab for this purpose.26 The pyridylaldehyde 14 was accessed in 5 steps and 28% overall yield from 6-fluoropyridin-3-ol, as outlined in the Supporting Information. The imine formation from 6-isopropoxy-2-nitronicotinaldehyde (14 to 15) proceeded smoothly in 94% yield. The Cadogan cyclization with the optimized conditions provided aza-indazole 16 in 55% yield on two consecutive 16 g scale reactions. Compound 16 was then selectively brominated to furnish 17 in 90% yield by leveraging the ortho guidance of the ether. Palladium-catalyzed carbonylation provided ester 18 in 84% yield, which was saponified to reveal the carboxylic acid 19, the strategic intermediate used to evaluate various aryl-amides (Scheme 2).

Scheme 2. Gram-Scale Synthesis of the Late-Stage Carboxylic Intermediate Containing the Bridged Ether Left-Hand-Side Substitution.

Scheme 2

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After identifying that the cyclopropyl substitution of the pyridone was optimal, the impact of small substituents on the cyclopropyl was evaluated (Table 4). There was a significant potency difference observed between cis-diastereomers 21 and 22, which were synthesized from enantiopure starting materials. Interestingly, the trans-diastereomers 20 and 23 had similar potency, and it should be noted that the absolute stereochemistry for these analogues is unassigned as they were obtained by SFC separation of the racemate. Compound 22 had a good solubility measured of 53 μg/mL at pH 6.8, but a slightly elevated clearance profile, while both trans-isomers demonstrated poor solubility. Further exploration of cis-substituted cyclopropanes led to the discovery of the fluoro-substituted cyclopropyl analogues 24 and 25 (Table 3, Figures 5 and 6). It was also observed that substituting the cyclopropyl group did not negatively impact MDR1 ER as seen when modifying the ether appendage, and this is reflected in their excellent rat brain Kpu, u. The biochemical potencies measured for analogues 22, 24, and 26 were likely at the lower limit of detection for the assay, and thus human whole blood potency was an important factor when evaluating compound advancement. In this regard, 24 was clearly superior in both total (31 nM) and PPB-corrected (2 nM) human whole blood potency. Additional profiling of 24 showed minimal MDR1 efflux, an excellent rat brain Kpu, u of 0.7, and acceptable solubility. Compound 26 had a similar profile but was slightly less potent in human whole blood and exhibited improved solubility. A Eurofin kinase panel was performed on compound 24 which showed an S(10) value of 0.077 at 1 μM based on 31 hits out of 403 nonmutant kinases tested (Figure 7), which is an excellent selectivity window relative to its picomolar IRAK4 biochemical potency.

Figure 5.

Figure 5

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Overlay of the cocrystal of the two cis-diastereoisomers of the fluorocyclopropyl pyridones. PDB codes 8TVN and 8TVM.

Figure 6.

Figure 6

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Focus on the fluoride region depicted with the pocket surface of compound 24 (yellow) and 25 (purple). PDB 8TVN and 8TVM.

Figure 7.

Figure 7

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Kinase selectivity tree of compound 24.

To understand the dramatic potency improvement obtained with the cis-fluorocyclopropyl diastereomer found in 24 and 26, X-ray cocrystal structures were obtained for potent analogue 24 and less potent diastereomer 25. The overlay in Figure 5 shows that the molecules are binding very similarly and that the only pronounced difference is the fluorocyclopropyl group. In Figure 6, this area is enlarged, and the blue mesh represents the protein surface surrounding the fluorocyclopropane in the two structures. In yellow, the fluorine of 24 is observed to enter perfectly a very narrow pocket formed by Ala211, Val200, Lys213, and the gatekeeper Tyr262. In purple, we can see that the fluorine of 25 pierces the pocket wall formed by Tyr262, in an apparent disruption to binding affinity.

In summary, it was found that the indazole and aza-indazole heterocyclic cores could be leveraged to reduce MDR1 efflux and improve brain penetration when compared to previously explored imidazopyrimidine cores. This was particularly important for the exploration of substitutions on the amide portion of the analogues where groups that had previously improved solubility had resulted in reduced CNS penetration. With this, we showed significant in vivo dose-dependent modulation of plasma and CNS pro-inflammatory cytokines IL-1b, TNFa, MCP-1, KC-GRO, and IL-6 using compound 6. The combination of the indazole and aza-indazole cores with the exploration of the N-substituted pyridones resulted in the identification of compound 24. Compound 24 demonstrates improved solubility to previous leads, such as compound 1, as well as increased brain penetration and exquisite potency in a human whole blood assay. This dramatic potency increase is attributed to the addition of a single precisely placed fluorine on the cyclopropylpyridone moiety, which projects perfectly into a previously unexplored pocket in the ATP-binding site. All of these SAR explorations were enabled by the optimization of chemistry to forge a highly substituted indazole core using a Cadogan cyclization, as well as a new streamlined synthesis of N-substituted-3-aminopyridones as previously reported by our group.15

Glossary

ABBREVIATIONS USED

CNS

central nervous system

hMics

human liver microsomes

hHeps

human hepatocytes

ICV

Intracerebroventricular injection

i.p.

intraperitoneal injections

IRAK4

Interleukin receptor associated kinase 4

LPS

lipopolysaccharide

MDR1 ER

P-glycoprotein mediated efflux ratio

PD

pharmacodynamic

PPB

plasma protein binding

Pgp

P-glycoprotein

TLR

Toll-like receptors

WB

whole blood.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00102.

  • Optimization of Cadogan cyclization; Kinomescan conducted at Eurofins Discovery for compound 24; Preparation and characterization of compounds; IRAK4 Biochemical Assay Description; Human Whole Blood Assay Procedures; MDR1–MDCK assay procedure; Kinetic Solubility Assay; Kpuu Assay; Determination of Fraction Unbound (Fu); X-ray Data collection and refinement statistics for 8TVN and 8TVM; Method for Protein Crystallography; Molecular formula string (PDF)

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ml4c00102_si_001.pdf (769KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ml4c00102_si_001.pdf (769KB, pdf)

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