Design, Synthesis, and Structure-Activity Relationship of Novel Potent and Highly Selective Cysteinyl Leukotriene Receptor 1 (CysLT1R) Antagonists

doi:10.6023/cjoc202306001

Abstract

Cysteinyl leukotrienes (CysLTs) are lipid mediators of inflammation, and their receptors (CysLTsR) play an essential role in asthma, allergic rhinitis, cancer, and other diseases. According to earlier studies, 3-substituted 1H-indole-2-car- boxylic acid derivatives displayed selective cysteinyl leukotriene receptor 1 (CysLT₁R) antagonistic activity, while their poor water solubility restricted their further evaluation. Hence, structural optimization was continued and multiple series of compounds were designed and synthesized based on existing research foundations. Among them, 3-(2-((E)-3-((3-((E)-2-(7-chloro- quinolin-2-yl)vinyl)phenyl)amino)-3-oxoprop-1-en-1-yl)phenyl)propanoic acid (T9) exhibits good selective CysLT₁ receptor antagonistic activity and improved solubility, with IC₅₀ value of (0.0066±0.0023) μmol/L and water solubility of 4.16×10^－5 g/mL.

Key words: cysteinyl leukotriene, cysteinyl leukotriene receptor 1 (CysLT₁R), selective antagonists

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Jingyi Wang, Jinyu Liu, Dongsheng Chen, Huayan Chen, Xin Xie, Fajun Nan. Design, Synthesis, and Structure-Activity Relationship of Novel Potent and Highly Selective Cysteinyl Leukotriene Receptor 1 (CysLT₁R) Antagonists[J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 259-276.

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Fig. & Tab. 16

Figure 1. Launched drugs of selective CysLT1 receptor antagonists

Scheme 1. Structure modification strategies

Scheme 2. Syntheses of compounds T1~T6 Reagents and conditions: (a) R/R1=CHO, tert-butyl(triphenylphosphoranylidene)acetate, toluene, reflux, overnight; (b) R/R1=Br, tert-butyl acrylate, Pd(OAc)2, PPh3, TEA, DMA, 100 ℃, 24 h; (c) TFA, DCM, 0 ℃~r.t., 4 h; (d) M2, HATU, DIPEA, DMF, r.t., overnight; (e) NaOH, EtOH, 50 ℃, overnight or NaOH, EtOH/THF/H2O, 50 ℃, overnight.

Compd.	IC₅₀^a/(μmol•L^－1)	Compd.	IC₅₀^a/(μmol•L^－1)
17g	0.13±0.023	T4	0.94±0.098
T1	0.35±0.12	T5	0.20±0.10
T2	0.85±0.14	T6	0.10±0.014
T3	2.77±0.50	Montelukast	0.057±0.029

Table 1. Effects of indole ring replacement on CysLT1R antagonistic activity

Scheme 3. Syntheses of compounds T7~T10 Reagents and conditions: (a) ethyl bromoacetate, Pd(OAc)2, P(Nap-1)3, K2CO3, THF, H2O, r.t., overnight; (b) tert-butyl(triphenylphospho- ranylidene)acetate, toluene, reflux, overnight; (c) TFA, DCM, 0 ℃~r.t., 4 h; (d) M2, HATU, DIPEA, DMF, r.t., overnight; (e) NaOH, EtOH, 50 ℃, overnight; (f) acryloyl chloride, DMAP, TEA, DCM, r.t., 1 h; (g) M3, Pd(OAc)2, P(o-tol)3, DIPEA, DMF, 100 ℃, 5 h; (h) LiOH?H2O, MeOH/THF/H2O, r.t., 2 h.

Compd.	R	IC₅₀^a/(μmol•L^－1)	Compd.	R	IC₅₀^a/(μmol•L^－1)
T7		0.24±0.098	T9		0.0066±0.0023
T8		0.038±0.0060	T10		0.037±0.0090

Table 2. Effects of carboxyl side chain on CysLT1R antagonistic activity

Scheme 4. Syntheses of compounds T11~T16 Reagents and conditions: (a) methyl bromoacetate, K2CO3, DMF, 80 ℃, overnight; (b) M3, Pd(OAc)2, P(o-tol)3, DIPEA, DMF, 100 ℃, 5 h; (c) LiOH?H2O, MeOH/THF/H2O, r.t., 2 h.

Compd.	IC₅₀^a/(μmol•L^－1)	Compd.	IC₅₀^a/(μmol•L^－1)
T11	0.068±0.013	T14	0.059±0.022
T12	0.13±0.032	T15	0.045±0.012
T13	0.075±0.00078	T16	0.039±0.0097

Table 3. Effects of heteroatom introduction on CysLT1R antagonistic activity

Scheme 5. Scaffold hopping strategy

Scheme 6. Syntheses of compounds T17~T20 Reagents and conditions: (a) PdCl2dppf?CH2Cl2, K2CO3, dioxane/H2O, 60 ℃, overnight; (b) tert-butyl bromoacetate, NaH, THF, 0 ℃~r.t., overnight; (c) M2, PdCl2dppf?CH2Cl2, Xantphos, CsCO3, dioxane, 80 ℃, overnight; (d) HCl/dioxane, 0 ℃~r.t., 4 h.

Scheme 7. Syntheses of compounds T21~T23 Reagents and conditions: (a) 2-chloro-4-pyridylboronic acid, PdCl2dppf?CH2Cl2, K2CO3, dioxane/H2O, 60 ℃, overnight; (b) M2, PdCl2dppf?CH2Cl2, Xantphos, CsCO3, dioxane, 80 ℃, overnight; (c) HCl/dioxane, 0 ℃~r.t., 4 h.

Scheme 8. Syntheses of compounds T24~T28 Reagents and conditions: (a) trimethyl borate, n-BuLi, THF, －78 ℃~r.t., 12 h; (b) 2-chloro-4-iodopyridine, PdCl2dppf?CH2Cl2, K2CO3, dioxane/H2O, 60 ℃, overnight; (c) 2-chloro-4-pyridylboronic acid, PdCl2dppf?CH2Cl2, K2CO3, dioxane/H2O, 60 ℃, overnight; (d) BBr3, DCM, －78 ℃~r.t., overnight; (e) tert-butyl bromoacetate, NaH, THF, 0 ℃~r.t., overnight; (f) M2, PdCl2dppf?CH2Cl2, Xantphos, CsCO3, dioxane, 80 ℃, overnight; (g) HCl/dioxane, 0 ℃~r.t., 4 h.

Scheme 9. Syntheses of compounds T29 and T30 Reagents and conditions: (a) methyl bromoacetate, NaH, THF, 0 ℃~r.t., overnight; (b) M2, Pd2dba3, Xantphos, CsCO3, dioxane, 80 ℃, overnight; (c) LiOH?H2O, MeOH/THF/H2O, r.t., 2 h; (d) Pd(OAc)2, TEA, DMF, 80 ℃, overnight; (e) NaOH, EtOH, 60 ℃, overnight.

Compd.	R	IC₅₀^a/(μmol•L^－1)	Compd.	R	IC₅₀^a/(μmol•L^－1)
T17		0.27±0.038	T24		0.075±0.0055
T18		0.070±0.0082	T25		0.60±0.024
T19		0.24±0.012	T26		1.37±0.037
T20		0.59±0.25	T27		0.0081±0.002
Compd.	R	IC₅₀^a/(μmol•L^－1)	Compd.	R	IC₅₀^a/(μmol•L^－1)
T21		0.13±0.041	T28		0.0025±0.0004
T22		0.39±0.070	T29		0.0057±0.001
T23		0.10±0.026	T30		0.010±0.0024

Table 4. Effects of scaffold hopping on CysLT1R antagonistic activity

Compd.	IC₅₀^a/(μmol•L^－1)
Compd.	CysLT₁R	CysLT₂R
17g	0.13±0.023	>100
T9	0.0066±0.0023	>100
T27	0.0081±0.002	8.75±1.14
T28	0.0025±0.0004	>100
T29	0.0057±0.001	>100
T30	0.010±0.0024	>100
Montelukast	0.057±0.029	>100

Table 5. Selectivity of CysLTs receptor subtypes

Compd.	Water solubility/(g•mL^－1)
17g	5×10^－6
T9	4.16×10^－5
T9 sodium salt	3.253×10^－2
T28	6.2×10^－7
T29	2.99×10^－5

Table 6. Water solubility of compounds

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新型选择性半胱氨酰白三烯受体1 (CysLT₁R)拮抗剂的设计合成及构效关系研究

Design, Synthesis, and Structure-Activity Relationship of Novel Potent and Highly Selective Cysteinyl Leukotriene Receptor 1 (CysLT₁R) Antagonists

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Fig. & Tab. 16

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新型选择性半胱氨酰白三烯受体1 (CysLT1R)拮抗剂的设计合成及构效关系研究