Quantitative structure-activity relationship study of ATP-sensitive potassium channel openers: Derivatives of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide

Figures & data

Figure 1 Structure of subsituted 4H-1,2,4-benzothiadiazine 1,1-dioxides.

Table I.  QSAR parameters and inhibitory and contractile activity of substituted 4H-1,2,4-benzothiadiazine 1,1-dioxides (See Figure1 for structure).

										pIC50(M)^a			pEC50(M)^b
S. No.	R3	R6	R7	ClogP(R3)	π6	π7	Vw7 (10^2 Å^3)	I3	I6	Obsd	Calcd Eq(2)	Prctd LOO	Obsd	Calcd Eq(4) Prctd	LOO
1	NH-Et	Cl	Cl	–0.09	0.71	0.71	0.244	0	1	6.60	6.54	6.53	5.96	5.39	5.32
2	NH-Pr	Cl	Cl	0.43	0.71	0.71	0.244	0	1	5.86	5.89	5.89	5.33	5.39	5.40
3	NH-iPr	Cl	Cl	0.21	0.71	0.71	0.244	1	1	6.55	6.62	6.63	5.64	5.39	5.36
4	NH-allyl	Cl	Cl	0.15	0.71	0.71	0.244	0	1	5.72	6.24	6.29	5.85	5.39	5.34
5	NH-cPr	Cl	Cl	–0.27	0.71	0.71	0.244	0	1	5.48	–^c	–^c	–^d	–^d	–^d
6	NH-cBu	Cl	Cl	0.29	0.71	0.71	0.244	0	1	5.90	6.06	6.08	4.90	–^c	–^c
7	NH-Et	Cl	Br	–0.09	0.71	0.86	0.287	0	1	6.57	6.45	6.42	5.57	5.61	5.61
8	NH-Pr	Cl	Br	0.21	0.71	0.86	0.287	1	1	6.59	6.52	6.51	5.25	5.61	5.67
9	NH-cBu	Cl	Br	0.29	0.71	0.86	0.287	0	1	5.92	5.97	5.98	5.18	5.61	5.68
10	NH-iPr	H	Cl	0.21	0.00	0.71	0.244	1	0	6.14	6.11	6.10	4.44	4.80	4.89
11	NH-iPr	H	Br	0.21	0.00	0.71	0.287	1	0	6.33	6.02	5.93	5.32	5.01	4.91
12	NH-Et	Cl	F	–0.09	0.71	0.14	0.115	0	1	6.70	6.82	6.87	4.37	4.57	4.59
13	NH-Pr	Cl	F	0.43	0.71	0.14	0.115	0	1	6.28	6.17	6.14	4.34	4.57	4.60
14	NH-iPr	Cl	F	0.21	0.71	0.14	0.115	1	1	6.80	6.90	6.95	4.38	4.57	4.59
15	NH-cBu	Cl	F	0.29	0.71	0.14	0.115	0	1	6.64	6.35	6.28	4.40	4.57	4.59
16	NH-Et	F	F	–0.09	0.14	0.14	0.115	0	0	6.43	6.32	6.23	4.18	4.09	4.08
17	NH-iPr	F	F	0.21	0.14	0.14	0.115	1	0	6.52	6.39	6.36	3.99	4.09	4.11
18	NH-iBu	F	F	0.83	0.14	0.14	0.115	0	1	5.25	5.16	5.11	–^d	–^d	–^d
19	NH-Et	Cl	OMe	–0.09	0.71	–0.02	0.304	0	1	6.32	6.41	6.43	–^c	–^c	–^c
20	NH-iPr	Cl	OMe	0.21	0.71	–0.02	0.304	1	1	6.62	6.49	6.45	4.43	4.34	4.32
21	NH-cBu	Cl	OMe	0.29	0.71	–0.02	0.304	0	1	6.29	5.93	5.87	4.63	4.34	4.28
22	NH-iPr	H	F	0.21	0.00	0.14	0.115	1	0	6.12	6.39	6.47	4.37	3.97	3.88
23	NH-iPr	H	OMe	0.21	0.00	–0.02	0.304	1	0	5.76	5.98	6.05	3.56	3.74	3.80
24^e	CH3	H	Cl	0.88	0.00	0.71	0.244	0	0	4.65	4.82	4.95	4.65	4.80	4.83

^a pIC₅₀ expressed as negative logarithm on molar basis, represents the inhibition of glucose-induced insulin secretion evaluated on isolated rat pancreatic islets

^b pEC₅₀ expressed as negative logarithm on molar basis, represents the contractile activity of KCl-depolarized rat aorta rings; taken from Ref. [38]

^{c “}Outlier” compound in the present study

^d Uncertain activity

^e Reference compound: diazoxide.

Table II.  Stepwise development of Equation (2) pIC₅₀(pancreas) =a₀ +a₁ClogP(R₃)+a₂Vw₇ +a₃ I₃ +a₄ I₆

a0	a1	a2	a3	a4	r	s	Fk,n–k-1^a	q^2	steps
6.553	–1.533( ± 0.50)				0.755	0.344	27.783	0.453	(i)
6.864	–1.584( ± 0.49)	–1.381( ± 1.56)			0.784	0.334	15.943	0.463	(ii)
6.777	–1.551( ± 0.46)	–1.486( ± 1.46)	0.263( ± 0.23)		0.824	0.312	13.426	0.517	(iii)
6.455	–1.254( ± 0.28)	–2.184( ± 0.86)	0.454( ± 0.14)	0.505( ± 0.16)	0.920	0.223	24.662	0.765	(iv)

^a The F statistics for n ( = 23) data-points and k ( = 1, 2, 3 & 4) independent variable(s).

Table III.  Intercorrelation matrix^a amongst independent variables of Equation (2).

	ClogP(R3)	Vw7	IR3	IR6
ClogP(R3)	1.000	0.115	0.069	0.303
Vw7		1.000	0.071	0.232
IR3			1.000	0.350
IR6				1.000

^a Matrix elements are the r-values.

Figure 2 Plot of observed versus calculated and predicted pIC₅₀ values.

de Tullio P, Boverie S, Becker B, Antoine M-H, Nguyen Q-A, Francotte P, Counerotte S, Sebille S, Pirotte B, Lebrun P. 3-Alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides as ATP-sensitive potassium channel openers: Effect of 6,7-disubstitution on potency and tissue selectivity. J Med Chem 2005; 48: 4990–5000

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