A quantitative structure-activity relationship study on matrix metalloproteinase inhibitors: Piperidine sulfonamide aryl hydroxamic acid analogs

Figures & data

Table I.  A series of piperidine sulfonamide aryl hydroxamic acid analogs (5) and related physicochemical parameter(s)

Compd	W	X	R^1	ClogP	I1	I1N
1	OCH3	OCH3	–(N[(CH2)2]2CH)–O–C6H4–4–CF3	2.520	1	0
2	OCH3	OCH3	–(N[(CH2)2]2CH)–O–C6H4–4–O–CF3	2.590	1	0
3	OCH3	OCH3	–(N[(CH2)2]2CH)–O–C6H4–2–O–CH3	1.130	0	0
4	OCH3	OCH3	–(N[(CH2)2]2CH)–O–C6H4–3–O–CH3	1.480	0	0
5	OCH3	OCH3	–(N[(CH2)2]2CH)–O–C6H4–4–O–CH3	1.480	1	0
6	OCH3	OCH3	–(N[(CH2)2]2CH)–O–C6H5	1.390	0	0
7	OCH3	OCH3	–(N[(CH2)2]2CH)–O–C6H4–4–Cl	2.250	1	0
8	OCH3	OCH3	–(N[(CH2)2]2CH)–O–piperonyl	1.430	0	0
9	–OCH2O–		–(N[(CH2)2]2CH)–O–C6H4–4–CF3	2.970	1	0
10	–OCH2O–		–(N[(CH2)2]2CH)–O–piperonyl	1.810	0	0
11	–OCH2CH2O–		–(N[(CH2)2]2CH)–O–C6H4–4–CF3	2.930	1	0
12	F	H	–(N[(CH2)2]2CH)–O–C6H4–4–CF3	2.670	1	0
13	Cl	H	–(N[(CH2)2]2CH)–O–C6H4–4–CF3	2.820	1	0
14	O(CH2)2–O–CH3	H	–(N[(CH2)2]2CH)–O–C6H4–4–CF3	2.780	1	0
15		H	–(N[(CH2)2]2CH)–O–C6H4–4–CF3	2.520	1	0
16	OCH3	H	–(N[(CH2)2]2CH)–O–C6H4–4–CF3	2.390	1	0
17	H	H	–(N[(CH2)2]2CH)–CH2–C6H5	2.940	0	0
18	H	H	–(N[(CH2)2]2CH)–C6H5	2.410	0	0
19	H	H	–(N[(CH2)2]2CH)–O–CH2–C6H4–4–CF3	2.360	0	0
20	H	H	–NH–C6H4–O–C6H5	2.400	0	1
21	H	H	–(N[(CH2)3]CH2)–NH–C(O)–C6H4–4–OCH3	1.080	0	1
22	H	H	–(N[(CH2)2]2CH)–O–C6H4–4–CF3	2.870	1	0
23	H	H	–(N[(CH2)2]2CH)–O–C6H4–4–OCF3	2.940	1	0
24	H	H	–(N[(CH2)3]CH2)–O–C6H4–4–CF3	2.930	0	0
25	H	H	–(N[(CH2)2]2N)–C(O)–C6H5	0.922	0	0
26	H	H	–(N[(CH2)2]2CH)–O–C6H4–4–CF3	2.670	1	0

Table II.  Observed and calculated MMP inhibitory potencies of compounds in Table 1. Observed activities have been taken from Ref. [23,24].

log (1/IC50)
	MMP-2			MMP-13
Compd	Obsd	Calcd, Equation 1	Loo	Obsd	Calcd, Equation 2	Loo
1	8.62	9.05	9.10	8.57	8.43	8.41
2	9.10	8.98	8.96	8.43	8.33	8.32
3	6.48	6.71	6.79	5.60	5.75	5.78
4	7.92	7.12	6.88	6.60	6.44	6.40
5	8.74	9.10	9.24	7.85	8.30	8.47
6	8.96^a	7.04	–	8.17^b	6.29	–
7	9.52	9.25	9.18	8.82	8.67	8.64
8	9.00^a	7.08	–	7.89^b	6.36	–
9	8.52	8.43	8.41	7.74	7.59	7.55
10	8.96^a	7.32	–	7.72	6.79	6.50
11	8.85	8.50	8.44	8.11	7.68	7.61
12	8.48	8.88	8.91	7.92	8.21	8.23
13	8.72	8.67	8.67	7.83	7.93	7.94
14	9.00	8.73	8.71	8.37	8.01	7.97
15	8.96	9.05	9.06	8.66	8.43	8.40
16	7.68^a	8.88	–	6.96^b	8.21	–
17	6.83	6.50	6.37	6.00	5.79	5.70
18	7.15	7.17	7.17	6.28^b	6.70	–
19	7.46	7.21	7.12	6.05	6.68	6.80
20	5.46	5.82	6.42	5.05	6.73	6.94
21	5.64	5.27	4.68	5.66	5.62	5.60
22	8.89	8.60	8.56	7.55	7.82	7.85
23	8.70	8.48	8.44	7.48	7.66	7.69
24	5.74	6.52	6.84	5.70	5.82	5.86
25	6.00	6.35	6.66	5.17	5.18	5.18
26	8.48	8.88	8.91	7.91	8.21	8.23

^a Not included in the derivation of Equation (1)

^b Not included in the derivation of Equation (2).

Barta TE, Becker DP, Bedell LJ, De Crescenzo GA, McDonald JJ, Mehta P, Munie GE, Villamil CI. Bioorg Med Chem Lett 2000; 11: 2481

 Web of Science ®Google Scholar

Barta TE, Becker DP, Bedell LJ, De Crescenzo GA, McDonald JJ, Munie GE, Rao S, Shieh HS, Stegeman R, Stevens AM, Villamil CI. Bioorg Med Chem Lett 2000; 10: 2815

 PubMedGoogle Scholar