JOURNALOF
MEDICINAL CHEMISTRY 0Copyright 1995 by the American Chemical Society
March 17, 1995
Volume 38, Number 6
Communications to the Editor N-(l-Methyl-5-indolyl)-N'-(3-methyl-5isothiazoly1)urea: A Novel, High-Affinity ~ - H T Receptor ~B Antagonist
Scheme 1" NH,.HCI
r=.( .._r
Ian T. Forbes,*?+Graham E. Jones,*%+ Olive E. Murphy,$ Victoria Holland,$ and Gordon S. Baxtert SmithKline Beecham Pharmaceuticals, Discovery Research, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, England
Received November 14, 1994
2 X=NMe, 80%
3
x=s,
83%
Reagents: (a) CDI, Et3N, CHzClz, 1 h, 0 "C; (b) DMF, 1 h, 120 "C.
rauwolscine do show some selectivity for ~ - H T over ~B 5-HTzc receptor^,^ they are not particularly useful as pharmacological tools as both compounds possess significant affinity at certain other 5-HT and non-5-HT receptors. The pyridylurea 1 (SB 200646A) has recently been reported as having mixed antagonist properties at cloned rat 5-HTzc receptors and at ~ - H T receptors ~B in the rat stomach fundus, but possessing selectivity over rat ~ - H T and ~ A a range of other recept~rs.~-'l In order
The 5-HTz family of receptors is comprised of .three sub-types, namely ~ - H T ~~A- H , T ~and B , 5-HTzc. These receptors have been grouped in the same class on the basis of molecular structure, signal transduction characteristics, and pharmaco1ogy.l ~ - H T receptors ~B are expressed in rat stomach fundus longitudinal muscle, where they mediate a contractile response to 5-HT,2,3 and also in rat jugular vein, where they mediate r e l a x a t i ~ n .The ~ mRNA transcript for 5-HTm receptors has been reported to occur in human brain, retina, liver, heart, kidney, small intestine, and other organ^,^ and a human ~ - H T receptor ~B has recently been c10ned.~)~ The ~ - H T ~ receptor B is very closely related to the Me .HCI 5-HTzc receptor, with which it shares a high degree of sequence homology2a,band very similar pharma~ology.~,~ 1 In view of this close similarity between ~ - H Treceptors ~B and 5-HTzc receptors, it is possible that some of the to identify the important physicochemical properties biological effects previously ascribed to activation or required for ~ - H T ~ caffinity / ~ B in this novel series, we antagonism of 5-HTzc receptors could in fact be due to have undertaken a comprehensive investigation of actions at ~ - H T receptors, ~B and, for example, it has structural variations around 1. We now report the recently been suggested that 5-HTm receptors may be synthesis of closely related isothiazolylureas, one of involved in the pathophysiology of migraine.8 Unforwhich displays marked selectivity for ~ - H T ~over B tunately, there is a complete lack of selective agents 5-HTzc and ~ - H T receptors. ~A which could be used t o probe the functional role of Compounds 2 and 3 were prepared as shown in ~ - H T ~receptors. B No selective agonists have been Scheme 1. 5-Amino-3-methylisothiazolehydrochloride reported, and although the antagonists yohimbine and was treated with 1,l'-carbonyldiimidazole (CDI) in the presence of triethylamine to give an intermediate which, * To whom correspondence should be addressed. after removal of the solvent, was reacted with either a Department of Medicinal Chemistry. in di5-aminoindoleg or a 5-aminoben~othiophene~~ * Department of Neurology. methylformamide (DMF) to give the isothiazolylureas. 5 Department of Psychiatry. +
0022-262319511838-0855$09.00/0
0 1995 American Chemical Society
Communications to the Editor
856 Journal of Medicinal Chemistry, 1995, Vol. 38, No. 6
Table 1. 5-HTm 5-HTzc, and ~ - H T z Receptor A Minities for Compounds 1-5 184-185 188-190 221-224 198-201 > 184 dec
1 2
3 4 5
7.41 f 0.06 (8) 7.95 ?C 0.11 (8) 7.82 f 0.15(4) 7.16 f 0.12 (6) 7.33 f 0.08 (3)
6.96 f 0.10 (3) 5.82 k 0.02 (4) 6.38 f 0.12 (4) 6.46 f 0.10 (3) 7.05 f 0.11 (6)
3 135 27 5 2
