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. 2020 Feb 27;11(4):528–534. doi: 10.1021/acsmedchemlett.9b00649

Discovery of [1,2,4]Triazolo[1,5-a]pyridine Derivatives as Potent and Orally Bioavailable RORγt Inverse Agonists

Ryota Nakajima †,*, Hiroyuki Oono †, Sakae Sugiyama †, Yohei Matsueda †, Tomohide Ida †, Shinji Kakuda †, Jun Hirata †, Atsushi Baba †, Akito Makino †, Ryo Matsuyama †, Ryan D White ‡, Ryan Ρ Wurz §, Youngsook Shin §, Xiaoshan Min #, Angel Guzman-Perez ‡, Zhulun Wang ∥, Antony Symons ⊥, Sanjay K Singh ∇, Srinivasa Reddy Mothe ∇, Sergei Belyakov ∇, Anjan Chakrabarti ∇, Satoshi Shuto ◆,○,*
PMCID: PMC7153279  PMID: 32292560

Abstract

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The retinoic acid receptor-related orphan nuclear receptor γt (RORγt), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. On the basis of the X-ray cocrystal structure of RORγt with 1a, an analogue of the known piperazine RORγt inverse agonist 1, triazolopyridine derivatives of 1 were designed and synthesized, and analogue 3a was found to be a potent RORγt inverse agonist. Structure–activity relationship studies on 3a, focusing on the treatment of its metabolically unstable cyclopentyl ring and the central piperazine core, led to a novel analogue, namely, 6-methyl-N-(7-methyl-8-(((2S,4S)-2-methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl)butanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a), which exhibited strong RORγt inhibitory activity and a favorable pharmacokinetic profile. Moreover, the in vitro and in vivo evaluation of 5a in a human whole-blood assay and a mouse IL-18/23-induced cytokine expression model revealed its robust and dose-dependent inhibitory effect on IL-17A production.

Keywords: Nuclear receptor, RORγt, triazolopyridine, inverse agonist

The retinoic acid receptor-related orphan nuclear receptor γt (RORγt) is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R.1,2 Therapies blocking IL-17A or IL-23R have successfully improved skin lesions in patients with moderate to severe psoriasis,3−7 thus rendering the RORγt inhibition a promising therapeutic target. After T0901317 was reported for its effective (albeit unselective) binding to RORγ,8 many RORγt antagonists (inverse agonists) have been developed,9−23 and several are already being clinically investigated as promising targets for the treatment of autoimmune diseases.24 Generally, nuclear receptors are proteins with highly conserved ligand binding domains (LBDs), which are structurally composed of α-helices that form a large lipophilic pocket responsible for binding small lipophilic ligands such as retinoid derivatives, fatty acids, cholesterol, and other lipophilic hormones and vitamins.25 Thus, one of the main challenges for drug delivery in this target class is the lipophilicity balance, which is required for strong LBD binding potency, while the metabolism associated with lipophilic small-molecule ligands should be minimized to afford favorable drug-like properties.

On the basis of a previous report describing a series of piperazine RORγt ligands,26 compound 1 (Figure 1) was selected as a starting point for further investigation, mainly because of its moderately low molecular weight (453) and lipophilicity (cLogD7.4 = 3.78). The optimization of 1 resulted in the new triazolopyridine derivative 3a (Table 1) that exhibited RORγt inverse agonist activity. Further optimization of 3a by modification of its metabolically unstable cyclopentyl ring and the central piperazine ring led to a new derivative, 6-methyl-N-(7-methyl-8-(((2S,4S)-2-methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl)butanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a) (see Table 3), which was indicated as the best candidate for further studies. Specifically, compound 5a exhibited potent RORγt inhibitory activity, a good pharmacokinetic (PK) profile in a mouse cassette dosing study, and dose-dependent inhibition of IL-17A production in a mouse IL-18/23-induced cytokine expression model. Herein the results of these studies are described.

Figure 1.

Figure 1

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Representative RORγt ligand 1 used as a reference in the current study.

Table 1. Structure–Activity Relationship (SAR) of the Triazolopyridine Series.

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compd R cLogD7.4a Luc IC50 (nM)b human LM CLint (mL min–1 mg–1)c
1 – 3.78 14 0.088
2a H 2.57 590 0.059
2b Me 2.53 8000  
3a H 2.37 41 0.032
3b Me 2.32 3200  
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a

Calculated using Pipeline Pilot 17.2.

b

Luciferase reporter gene assay used for the evaluation of the RORγt transcriptional activity inhibition. The employed HEK293T cells were transfected with GAL4-NR-luciferase plasmids, and the activity was evaluated using the Dual-GLOTM Luciferase Assay System.

c

Metabolic stability in liver microsome (LM).

Table 3. RORγt Inhibitory Activity and Lipophilicity of Analogues 5a and 5b.

graphic file with name ml9b00649_0007.jpg

graphic file with name ml9b00649_0008.jpg

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a

Calculated using Pipeline Pilot 17.2.

b

Luciferase reporter gene assay to assess the RORγt transcriptional activity inhibition. The employed HEK293T cells were transfected with GAL4-NR-luciferase plasmids, and the activity was evaluated using the Dual-GLOTM Luciferase Assay System.

c

Metabolic stability in liver microsome.

An X-ray cocrystal structure of human RORγt with 1a (Figure 2C), an analogue of the piperazine RORγt ligand 1, was successfully obtained (PDB ID 6O3Z; Figure 2).27,28 As illustrated in Figure 2A, the cyano group of 1a forms hydrogen bonds with Arg367 and Leu287, while the amide NH group forms a hydrogen bond with Phe378. Furthermore, a hydrogen bond was developed between the fluorobenzene ring and the hydroxyl group of Ser404, where a small space around the 4- and 5-positions of the ring was detected (Figure 2B). Considering this additional space in the pocket, the phenyl ring of compound 1 could be replaced by a nitrogen-containing bicyclic ring to simultaneously decrease the overall lipophilicity and facilitate the hydrogen-bonding interactions with Ser404, thus allowing a more detailed investigation of this residue. The previous report by Hintermann and co-workers described a weakly lipophilic triazolopyridine derivative having an N-([1,2,4]triazolo[4,3-a]pyridin-6-yl)amide moiety, which displayed moderate inhibitory activity in the reporter gene assay and good liver microsomal stability.29 This triazolopyridine derivative demonstrated that a nitrogen-containing bicyclic ring was tolerable for the RORγt inhibitory activity, which led us into detailed investigation with other chemotypes of triazolopyridine analogues.

Figure 2.

Figure 2

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X-ray cocrystal structure of RORγt with compound 1a (PDB ID 6O3Z). (A) RORγt-LBD and compound 1a, depicted in gray and green, respectively. Green dashes represent the hydrogen-bonding interactions. (A) The red circle indicates the small space around the 4- and 5-positions of the fluorobenzene ring of 1a. The surface of the RORγt-LBD site (gray) and the surface of 1a (green) were calculated from the X-ray structure. (C) Molecular structure of 1a.

To that end, two series of analogues bearing N-([1,2,4]triazolo[4,3-a]pyridin-7-yl)amide and N-([1,2,4]triazolo[1,5-a]pyridin-6-yl)amide moieties were synthesized. Since it has been reported that RORγt is constitutively active in the absence of an endogenous ligand,30 all of the compounds were evaluated in a luciferase reporter gene assay without a control agonist ligand to assess their RORγt inverse agonist activity.

Moreover, all of the synthesized triazolopyridine analogues were designed to achieve a lower lipophilicity than compound 1 (cLogD7.4 = 3.78). As outlined in Table 1, the cLogD7.4 values of the novel analogues were successfully decreased by approximately 1 unit relative to 1. However, the [1,2,4]triazolo[4,3-a]pyridine derivative 2a displayed reduced inhibitory activity in the reporter gene assay (IC50 = 590 nM), whereas the [1,2,4]triazolo[1,5-a]pyridine derivative 3a retained an excellent inhibitory activity (IC50 = 41 nM), comparable to that of compound 1, indicating that the nitrogen atoms in the [1,2,4]triazolo[1,5-a]pyridine ring were well-tolerated for the inhibition of the RORγt transcriptional activity. Furthermore, although 3a improved the human liver microsome (LM) stability (human CLint = 0.032 mL min–1 mg–1), the methyl-substituted triazolopyridine derivatives 2b and 3b exhibited lower in vitro activity, probably due to steric repulsions in the binding pocket. Moreover, the X-ray analysis results implied that only unsubstituted triazolopyridine rings are acceptable because the available space at the 4- and 5-positions of the fluorobenzene ring of 1a is small. Therefore, compound 3a, which exhibited the most improved LM stability and high potency, was further optimized.

To elucidate the PK profile of 3a, this compound was incubated in human hepatocytes, and its metabolites were explored by mass spectrometry (MS). During the MS analysis, no glutathione adducts were detected, suggesting a low tendency toward the formation of reactive metabolites, while no metabolic soft spots on the central triazolopyridine core could be observed, thus supporting the suitability of the triazolopyridine moiety as a lead scaffold. In contrast, oxidative adducts were detected on the cyclopentyl ring, which prompted us to further optimize analogue 3a.

A series of 3a analogues were designed by exploring cyclopentyl ring alternatives and acyclic chains bearing fluorine atoms that could potentially block the metabolism. The SAR results of the cyclopentyl ring modifications in analogue 3a are summarized in Table 2. Although the substitution of two fluorine atoms on the cyclopentyl ring (4a) improved the cLogD7.4 and LM stability, the reporter gene inhibitory activity of RORγt was slightly decreased (IC50 = 130 nM). Similarly, replacing the cyclopentyl ring by a pyran ring (4b) significantly decreased the inhibitory activity. Moreover, the phenyl derivative 4c had similar LM stability (human CLint = 0.021 mL min–1 mg–1) compared to 3a, but its inhibitory activity was slightly lower (IC50 = 79 nM). The cyclopentyl ring of 3a was then replaced by branched or unbranched alkyl chains, resulting in derivatives 4d–g. The inhibitory activity of the isopropyl analogue (4d) was slightly decreased (IC50 = 230 nM), whereas the isobutyl derivative 4e had inhibitory activity (IC50 = 59 nM) and LM stability comparable to those of 3a. Since the trifluoromethyl group is often used instead of a methyl group to decrease the oxidative metabolism or increase the steric size, the two methyl groups of 4e were replaced by trifluoromethyl groups (4f), resulting in similar inhibitory activity (IC50 = 50 nM) and improved LM stability. Moreover, the results for monotrifluoromethyl derivative 4g (IC50 = 240 nM) proved that the double substitution was more favorable for the inhibitory activity. Hence, compound 4f was selected for further investigation

Table 2. SAR of the 3a Derivatives.

graphic file with name ml9b00649_0005.jpg

graphic file with name ml9b00649_0006.jpg

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a

Calculated using Pipeline Pilot 17.2.

b

Luciferase reporter gene assay to assess the RORγt transcriptional activity inhibition. The employed HEK293T cells were transfected with GAL4-NR-luciferase plasmids, and the activity was evaluated using the Dual-GLOTM Luciferase Assay System.

c

Metabolic stability in liver microsome.

To improve the activity of 4f, the 2-methylpyridine moiety was replaced by substituted pyridines or other heteroaryl rings (data not shown). However, this structural modification did not improve either the inhibitory activity or the lipophilicity of the obtained analogues. Therefore, the piperazine moiety of 4f was replaced by piperidine to retain a low lipophilicity value, and an ether linkage was introduced between the piperidine ring and the triazolopyridine ring. The cis- and trans-piperidine analogues 5a and 5b were thus obtained, with cLogD7.4 values of 2.67 (Table 3). Interestingly, 5a maintained good RORγt inhibitory activity (IC50 = 51 nM) and LM stability (human CLint = 0.010 mL min–1 mg–1) compared with 4f, whereas the inhibitory activity of 5b was insignificant. Furthermore, the in vitro absorption, distribution, metabolism, and excretion (ADME) profiles of compounds 1, 3a, 4f, and 5a were assessed (Table 4). Compounds 3a, 4f, and 5a displayed better microsomal stability than compound 1 (human CLint = 0.032, <0.010, and 0.010 mL min–1 mg–1, respectively) along with decreased plasma protein binding (PPB) rates (77.3%, 86.1%, and 91.8%, respectively). Moreover, compounds 4f and 5a were sufficiently soluble in an aqueous medium. Although 3a and 4f exhibited low Caco-2 permeability in the apical-to-basolateral (A-to-B) direction, 5a displayed efficient permeability in the same evaluation system.

Table 4. In Vitro ADME Profiles of Compounds 1, 3a, 4f, and 5a.

  LM CLint (mL min–1 mg–1)a
 PPB (%)b
   Caco-2 Papp (10–6 cm/s)d
compd human mouse human mouse solubility (μM)c A-to-B B-to-A
1 0.088 0.11 99.7 95.7e 71 40 55
3a 0.032 0.011 77.3 78.8 190 2.5 46
4f <0.010 <0.010 86.1 76.7 200 9.6 36
5a 0.010 0.030 91.8 86.5 170 31 51
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a

Metabolic stability in liver microsome.

b

Plasma protein binding using human or mouse plasma.

c

The second fluid of the Disintegration Test of the Japanese Pharmacopoeia (pH 6.8) was used.

d

Permeability in the apical-to-basolateral (A-to-B) direction and vice versa (B-to-A).

e

Compound 1 might be unstable in the mouse PPB assay.

The in vivo PK profiles of compounds 1, 3a, 4f, and 5a were investigated in mice using cassette dosing (Table 5). Compared with compound 1, compounds 4f and 5a showed improved bioavailability (BA > 100%), notably lower unbound clearance (CLu = 1.1 L h–1 kg–1 for 5a), and higher area under the curve (AUC) (around 31-fold higher than for 1 in the case of 5a) and t1/2 (>3 h for 5a). Because of the favorable in vitro activity and ADME profile, analogue 5a was further investigated.

Table 5. PK Profiles of Compounds 1, 3a, 4f, and 5a in a Mouse Cassette Dosing Studya.

          t1/2 (h)
compd BA (%) AUC p.o. (nM h) CL/CLu (L h–1 kg–1) VDss (L/kg) p.o. i.v.
1 48 490 2.0/46 1.6 0.7 0.7
3a 47 840 1.1/5.3 0.77 1.2 1.4
4f 110 2300 1.1/4.5 1.1 1.1 1.0
5a 120 15000 0.15/1.1 0.80 3.6 3.9
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a

2 μmol/kg p.o. dose and 1 μmol/kg i.v. dose.

A human whole-blood assay of compound 5a was conducted to assess its inhibitory activity against the T-cell receptor-dependent production of IL-17A in human whole blood. It was proven that compound 5a suppressed the IL-17A production in a dose-dependent manner with an IC50 value of 130 nM (Figure 3A). The in vivo potency of 5a toward modulation of the cytokine production through the suppression of the differentiation and activation of Th17 and Th1/17 cells was assessed using an in vivo mouse IL-18/23-induced cytokine expression model. Compound 5a was orally administered once 3 h prior to the IL-18/23 injection, and the IL-17A level in blood was measured 4 h after the injection of IL-18/23. As illustrated in Figure 3B, 5a achieved a dose-dependent inhibition of the IL-17A production in 3, 10, 30, and 100 mg/kg doses.

Figure 3.

Figure 3

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(A) Human whole-blood assay (n = 2). Human whole blood was diluted 2-fold with RPMI 1640 medium and stimulated using anti-CD3 and anti-CD28 monoclonal antibodies, IL-18, and IL-23, followed by treatment with 5a. The level of IL-17A in the culture medium was measured after 2 days. (B) In vivo mouse IL-18/23-induced cytokine expression model. Mice were administered orally once with a vehicle (0.5% MC400) or 5a. After 3 h, the mice were subjected to intraperitoneal administration of 2 μg of mIL-18 (Medical & Biological Laboratories) and 1 μg of mIL-23 (R&D Systems). A blood sample was collected 4 h later, and the IL-17A concentration in the plasma was measured.

In summary, the new triazolopyridine derivative 3a was identified as a potent RORγt inhibitor. Optimization of the metabolic soft spots on the cyclopentyl ring of 3a followed by optimization of the piperazine ring led to a novel analogue, namely, 6-methyl-N-(7-methyl-8-(((2S,4S)-2-methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl)butanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a), which exhibited potent RORγt inhibition in a luciferase reporter gene assay as well as in a human whole-blood assay measuring IL-17A release. Moreover, a robust PK profile allowed the in vivo evaluation in an IL-18/23-induced cytokine expression mouse model, where 5a significantly inhibited the production of IL-17A in a dose-dependent manner.

Acknowledgments

We thank Keiko Shimada for her help with computational chemistry, Mariko Hirano, Yukiko Enomoto, and Akiko Takeuchi for the pharmacological discussion, Kevin Gaida for the whole-blood assay development and support, Shon Booker for chemistry optimization, and Steve Thibault and Haoda Xu for the protein supply.

Glossary

Abbreviations

BA

bioavailability

RORγt

retinoic acid receptor-related orphan receptor γt.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00649.

  • Synthetic procedures, compound characterization, crystallography studies, and assay descriptions (PDF)

Author Present Address

▲ R.N.: Teijin Limited, 2-1 Kasumigaseki 3-chome, Chiyoda-ku, Tokyo 100-8585, Japan.

Author Present Address

S.K.S.; AWAK Technologies, 3 Tuas Lane, Singapore 638612.

Author Present Address

★ S.R.M.: Polymer Engineering Characterization, Institute of Chemical and Engineering Sciences, Agency of Science, Technology and Research, 1 Pesek Road, Jurong Island, Singapore 627833.

Author Present Address

■ S.B.: Wintershine Health and Skincare Pte Ltd., 23 Goldhill Pl., Singapore 308931.

Author Present Address

+ A.C.: Syngene International Limited, Biocon Park SEZ, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.

Author Contributions

These authors contributed equally.

The authors declare no competing financial interest.

Supplementary Material

ml9b00649_si_001.pdf (5.2MB, pdf)

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