Design, synthesis and biological evaluation of novel inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitors

Figures & data

Figure 1. Chemical structures of select IMPDH inhibitors used for the pharmacophore model development12.

Figure 2. The five-point pharmacophore model – AADHR – for IMPDH inhibitors with VX-148 (3, Figure 1) and the design strategy based on 3 (Parts A, B and C) utilized for systematic modifications. A: Acceptor (light pink); D: Donor (cyan); H: Hydrophobic (green) and R: Ring (orange) features.

Table 1. In vitro inhibitory and cellular potencies of Part A modifications.

Compound	Part A	IMPDH II pIC50	PBMC proliferation inhibition (pIC50)	Reversal of PBMC inhibition by GMP (%)
1 (MPA)*	–	6.89	6.9	100
2 (VX-497)*	–	8.46	6.6	100
3 (VX-148)*	4-cyano-3-methoxyphenyl	6.42	7.06	100
13	3,4-dimethoxyphenyl	6.63	6.25	84
14	3-methoxy-4-methylphenyl	4.71	<5	–
15	3-methoxy-4-morpholin-4-yl-phenyl	<4.5	<5	–
16	4-(3,6-dihydro-2H-pyran-4-yl-3-methoxyphenyl	5.45	5.23	45
17	3-methoxy-4-(tetrahydropyran4-yl)phenyl	<4.5	NT†	–
18	2,3-dihydrobenzofuran-6-yl	4.98	<5	–
19	2,3-dihydrobenzo[1,4]dioxin-6-yl	<4.5	<5	–
20	3,4-methylenedioxyphenyl	>4.5	5.44	0
21	1-methyl-1H-benzoimidazol-5-yl	4.84	5.45	0
22	3-methoxyquinoxalin-6-yl	<4.5	5.27	0
23	2,3-dimethoxynaphathalen-6-yl	<4.5	5.53	19
24	3-methyl-2,3-dihydrobenzofuran-5-yl	<4.5	<5	–
25	4-methoxyquinazolin-6-yl	<4.5	5.5	0
26	2-methyl-4-chromenon-7-yl	<4.5	5.38	0
27	4-chromenon-7-yl	<5	<5	–

*Refer Figure 1 for structures.

†Not tested.

Scheme 1. Syntheses of compounds 13–27. Reagents and conditions: (a) NaBH₄, EtOH, RT; (b) DPPA, DBU, toluene; (c) PPh₃, THF:Water; (d) L-(+)-tartaric acid, MeOH; (e) NaOH, EtOAc; (f) H₂, Pd(OH)₂/C, EtOH; (g) KCN, DMSO; (h) 10, CDI, EtOAc, RT; (i) phenyl chloroformate, DCM, RT; (j) DIPEA, EtOAc, RT; (k) DCM, RT, 6 h.

Scheme 2. Syntheses of compounds 30–35. Reagents and conditions: (a) DCM, RT; (b) (i) CuSO₄:SiO₂; (ii) methanolic NH₃, THF; (c) MeI, K₂CO₃, acetone; (d) NaNHCN, 2-propanol, 80 °C, 1 h; (e)1,1′-thiocarbonyldi-2(1H)-pyridone, DCM, RT; (f) (i) HCl:1,4-dioxane, RT; (ii) 11b, CDI, EtOAc, RT; (g) MeI, DMF, RT; (h) EtOH, reflux.

Scheme 3. Syntheses of compounds 36–39. Reagents and conditions: (a) KI (cat.), AcCN, RT; (b) HATU, DIPEA, THF, RT.

Scheme 4. Syntheses of compounds 40–44. Reagents and conditions: (a) NaH, THF, reflux; (b) DIPEA, THF, RT; (c) 1,1′-carbonothionyldipyri-din-2(1H)-one, DCM, RT; (d) silver trifluoroacetate, TEA, AcCN, reflux; (e) HATU, DIPEA, THF, RT; (f) (i) DCM, RT; (ii) HgO, S, EtOH, reflux.

Scheme 5. Syntheses of compounds 45–53. Reagents and conditions: (a) (i) DCM, RT; (ii) MeI, K₂CO₃, RT; (b) NaNHCN, 2-propanol, reflux; (c) LiOH, THF:H₂O (2:1), RT.

Scheme 6. Syntheses of compounds 54–60. Reagents and conditions: (a) 3-Bromoaniline, DCM, RT; (b) MeI, K₂CO₃, RT; (c) NaNHCN, 2-propanol, reflux; (d) substituted arylboronic acid, Cs₂CO₃, SPhos, Pd(OAc)₂/EtOAc:toluene (1:1), 100 °C.

Table 2. In vitro inhibitory and cellular potencies of Part B modifications.

Compound	R1	Part B	IMPDH II pIC50	PBMC proliferation inhibition (pIC50)	Reversal of PBMC inhibition by GMP (%)
30	CN		<4.5	<5	–
31	OMe		<4.5	<5	–
32	CN		5.6	5.38	100
33	OMe		5.25	<5	–
34	CN		<4.5	NT	–
35	OMe		<4.5	<5	–
36	OMe		<4.5	<5	–
37	CN		<4.5	<5	–
38	CN		<4.5	<5	–
39	OMe		<4.5	<5	–
40	OMe		<4.5	<5	–
41	CN		<4.5	<5	–
42	CN		4.61	<5	–
43	CN		<4.5	5.87	0
44	CN		<4.5	5.41	0

NT, not tested.

Table 3. In vitro inhibitory and cellular potencies of Part C modifications.

Compound	R3	IMPDH II pIC50	PBMC proliferation inhibition (pIC50)	Reversal of PBMC inhibition by GMP (%)
45	–OCH2COOCH(CH3)	<4.5	<5	–
46	–OCH2COOH	<4.5	<5	–
47	2-methyl-2H-tetrazol-5-yl	<4.5	<5	–
48	1-methyl-1H-tetrazol-5-yl	<4.5	<5	–
49	(2-methyl-2H-tetrazol-5-yl)-methyl	<4.5	<5	–
50	–CH2CH2COOH	<4.5	<5	–
51	–CH=CHCOOH	<4.5	<5	–
52	–CH2COOH	<4.5	NT	–
53	–COOH	<4.5	NT	–
54	2-fluorophenyl	<4.5	<5	–
55	3-flurophenyl	<4.5	<5	–
56	4-fluorophenyl	<4.5	<5	–
57	3-(trifluoromethyl)phenyl	<4.5	<5	–
58	3-carboxyphenyl	<4.5	NT	–
59	4-cyanophenyl	<4.5	<5	–
60	3-cyanophenyl	<4.5	5.0	–

NT, not tested.

Dhar TG, Shen Z, Gu HH, et al. 3-Cyanoindole-based inhibitors of inosine monophosphate dehydrogenase: synthesis and initial structure-activity relationships. Bioorg Med Chem Lett 2003;13:3557–60

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