Synthesis and biological evaluation of novel N₁-phenylsulphonyl indole derivatives as potent and selective 5-HT₆R ligands for the treatment of cognitive disorders

Figures & data

Figure 1. Structures of 5-HT₆R antagonists in clinical trials for Alzheimer’s disease.

Figure 2. Structures of known 5-HT₆ receptor ligands.

Figure 3. 5-HT₆ receptor pharmacophore model.

Figure 4. General structure of designed 5-HT₆ receptor ligands.

Scheme I. Reagents and conditions: (a) NaH, tetrahydrofuran, RT, 20–24 h; (b) LiAlH₄, 0–5 °C, 4–5 h; (c) MnO₂, Ethylene Dichloride, reflux, 3–4 h; (d) N-methyl (or) N-ethyl piperazine, Ethylene Dichloride, Na(OAC)₃BH, RT, 6–7 h; (e) Methanolic HCl (16% w/v), Diethylether, RT, 1 h.

Table 1. 5-HT₆R binding data† for compounds 6.

Comp. No	R^1	R^2	R^3	R^4	% Inhibition at 100 nM concentration*	Ki (nM)
6a	H	H	H	CH3	92.41	7.50 ± 0.42
6b	H	H	CH3	CH3	95.11	7.01 ± 0.26
6c	H	H	CH3	C2H5	95.48	3.96 ± 0.28
6d	H	H	Cl	CH3	92.36	18.4 ± 0.84
6e	H	H	Cl	C2H5	92.06	15.6 ± 0.70
6f	H	H	Br	CH3	88.79	–
6g	H	H	Br	C2H5	87.68	–
6h	5-OCH3	H	H	CH3	67.58	–
6i	5-OC2H5	H	H	CH3	63.73	–
6j	5-O^iPr	H	H	CH3	61.48	–
6k	5-F	H	H	CH3	79.20	–
6l	5-OCH3	H	CH3	CH3	62.18	–
6m	5-F	H	CH3	CH3	86.18	–
6n	5-F	H	CH3	C2H5	78.54	–
6o	5-F	H	Cl	CH3	72.97	–
6p	5-F	H	Cl	C2H5	64.82	–
6q	5-F	H	Br	CH3	70.45	–
6r	5-F	H	Br	C2H5	62.52	–
6s	5-Br	H	Br	C2H5	55.86	–
6t	5-OCH3	H	Cl	CH3	57.03	–
6u	5-OCH3	H	Cl	C2H5	55.68	–
6v	5-OCH3	H	Br	CH3	54.21	–
6w	5-OCH3	H	Br	C2H5	50.53	–
6x	H	CH3	Cl	CH3	96.63	5.45 ± 0.28
6y	H	CH3	Cl	C2H5	92.91	7.85 ± 0.35
6z	H	CH3	Br	CH3	93.23	9.11 ± 0.24
6aa	H	CH3	Br	C2H5	91.51	12.8 ± 0.63
6ab	5-OCH3	CH3	Cl	CH3	71.53	–
6ac	5-OCH3	CH3	Cl	C2H5	68.10	–

*The data represent average of two determinations.

†5-HT₆ receptor-binding studies were carried out at NovaScreen Biosciences Corporation, (caliper life sciences), Hanover, MD, USA. Human recombinant/HEK293 cells; Radioligand: [³H] LSD (60–80 Ci/mmol).

“^_” means not tested for K_i (nM) determination.

Table 2. Pharmacokinetic profile of compounds 6b, 6c, and 6x in male wistar rats*.

Compound	6b	6c	6x
i.v. (n = 3)
Dose (mg/kg)	10	10	10
t1/2 (h)	2.69 ± 1.51	6.25 ± 0.35	5.84 ± 2.21
Vz (L/kg)	3.6 ± 1.2	6.9 ± 4.3	7.5 ± 1.0
Cl (mL/min/kg)	34 ± 12	40 ± 7	52 ± 7
p.o. (n = 3)
Dose (mg/kg)	10	10	10
t1/2 (h)	7.85 ± 2.62	3.18 ± 1.71	1.73 ± 0.56
Cmax (ng/mL)	1375 ± 427	749 ± 836	106 ± 1
Tmax (h)	0.38 ± 0.18	0.50 ± 0.43	0.38 ± 0.18
AUC (ng.h/mL)	3194 ± 1748	1171 ± 1046	342 ± 152
F (%)	30 ± 7	14 ± 10	10 ± 6
Brain (ng/g)	570 ± 145	312 ± 82	486 ± 250
Plasma (ng/mL)	286 ± 80	592 ± 37	293 ± 102
Cb/Cp	2.03 ± 0.42	0.53 ± 0.13	1.61 ± 0.39

*Fasted male wistar rats, vehicle used: water for injection for both oral and intravenous routes. Dosing volumes: 10 mL/kg p.o. and 2 mL/kg for i.v.; values are mean ± SD.

i.v. = intravenous, p.o. = per oral, t_1/2 = half-life, Vz = volume of distribution, Cl = clearance, C_max = The peak plasma concentration of a drug after administration, T_max = Time of maximum drug concentration, AUC = Area Under the Curve, F (%) = bioavailability, C_b/C_p = brain to plasma ratio.

Table 3. Human CYP45045 inhibitory data and microsomal metabolic stability for compound 6b*.

	IC50 (µM)		% Metabolism in liver microsomes
Compound	CYP 3A4	CYP 2D6	Human	Rat
6b	6.9	4.3	94	100

*The cytochrome P450 inhibitory potential was determined using isoform-selective assays and heterologously expressed human CYP 2D6 and CYP 3A4. These values are the mean of duplicate determinations. Microsomal metabolic stability in wistar rat and human at 0.5 h, conc. 2.5 µM.

Figure 5. Novel object recognition test data for compound 6b in rats. Compound 6b versus vehicle (paired t-test), n = 9–10/group, p.o., dosing drug: 60 min prior to test (p.o.). Vehicle PEG 400 50% v/v; 1 mL/kg, p.o. *p < 0.05 Student’s t-test. D.I. = discriminative index.

Lewis DFV, Cytochromes P. Structure, function and mechanism. London: Taylor and Francis Publishing; 1996

 Google Scholar