123944-91-2Relevant academic research and scientific papers
Computer-Aided Design and Synthesis of 5-Substituted Tryptamines and Their Pharmacology at the 5-HT1D Receptor: Discovery of Compounds with Potential Anti-Migraine Properties
Glen, Robert C.,Martin, Graeme R.,Hill, Alan P.,Hyde, Richard M.,Woollard, Patrick M.,et al.
, p. 3566 - 3580 (2007/10/03)
The design and synthesis of a series of novel 5-substituted tryptamines with pharmacological activity at 5-HT1D and other monoamine receptors is described.Structural modifications of N- and C-linked (prinicipally hydantoin) analogues at the 5-position were synthesized and their pharmacological activities were utilized to deduce significant steric and electrostatic requirements of the 5-HT1D and 5-HT2A receptor subtypes.Conformations of the active molecules were computed which, when overlaid, suggested a pharmacophore hypothesis which was consistent with the affinity and selectivity measured at 5-HT1D and 5-HT2A receptors.This pharmacophore is composed of a protonated amine site, an aromatic site, a hydrophobic pocket, and two hydrogen-bonding sites.A 'selectively site' was also identified which, if occupied, induced selectivity for 5-HT1D over 5-HT2A in this series of molecules.The development and use of the pharmacophore models in compound design is described.In addition, the physicochemical constraints of molecular size and hydrophobicity required for efficient oral absorption are discussed.Utilizing the pharmacophore model in conjuction with the physicochemical constraints of molecular size and log DpH7.4 led to the discovery of 311C90 (6), a new selective 5-HT1D agonist with good oral absorption and potential use in the treatment of migraine.
Therapeutic substituted indole compounds and compositions thereof
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, (2008/06/13)
The present invention is concerned with compounds of formula (I) STR1 wherein R, R1 and R2 are independently selected from hydrogen and C1-4 alkyl; R3 and R4 are independently selected from hydrogen, C1-6 alkyl (including cycloalkyl) and aryl (wherein the alkyl or aryl group, which latter includes benzyl, is optionally substituted by one or more atoms or groups independently selected from halogen, C1-4 alkyl and aryl), provided R3 benzyl or substituted benzyl when R4 =H; m is an integer of from 0 to 2; n is an integer of from 0 to 3; (W) is a group of formula (i), (ii), (iii), or (iv) STR2 wherein Y is selected from oxygen, methylene and >N--R5, where R5 is hydrogen, C1-4 alkyl, or benzyl, Z and Z' are independently selected from >C=O, >C=S and methylene, and the chiral center * in formula (i) or (ii) is in its (S) or (R) form or is a mixture thereof in any proportions; X is a group selected from aryl (including heteroaryl) xanthenyl dibenzofuranyl which group is optionally substituted; and salts and solvates thereof, the preparation of these compounds, pharmaceutical formulations containing them and their use in medicine, particularly in the treatment of migraine.
