Neurogen Corporation

Xiao-shu He

Brian De Costa

Alan J Hutchison

Andrew Y Thurkauf

He Zhao

Jan William Wasley

George D Maynard

Robert W DeSimone

John M Peterson

Jan W F Wasley

Xiaoyan Zhang

James E Krause

Robbin M Brodbeck

Kenneth Shaw

Rajagopal Bakthavatchalam

Xi Chen

Linda M Gustavson

Taeyoung Yoon

Kevin J Hodgetts

Dario Doller

Stanislaw Rachwal

Yiping Shen

Timothy M Caldwell

Wallace C Pringle

Cheryl K Steenstra

Helen Yin

Jan Wf Wasley

This invention relates to low molecular weight, non-peptidic, non-peptidomimetic, organic molecules that act as modulators of mammalian complement C5a receptors, preferably ones that act as high affinity C5a receptor ligands and also to such ligands that act as antagonists or inverse agonists of complement C5a receptors. Preferred compounds of the invention possess some or all of the following properties in that they are: 1) multi-aryl in structure, 2) heteroaryl in structure, 3) a pharmaceutically acceptable oral dose can provide a detectable in vitro effect, 4) comprise fewer than four or preferably no amide bonds, and 5) capable of inhibiting leukocyte chemotaxis at nanomolar or sub-nanomolar concentrations. This invention also relates to pharmaceutical compositions comprising such compounds and the use of such compounds in treating a variety of inflammatory and immune system disorders. Additionally, this invention relates to the use such compounds as probes for the localization of C5a receptors.

High affinity small molecule C5a receptor modulators

Melanin concentrating hormone receptor ligands (especially 1-benzyl-4-aryl-piperazines, 1-benzyl-4-aryl-piperidines and related compounds), capable of modulating MCH receptor activity, are provided. Such ligands may be used to modulate MCH binding to MCH receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of metabolic, feeding and sexual disorders in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting MCH receptors (e.g., receptor localization studies).

Melanin concentrating hormone receptor ligands: substituted 1-benzyl-4-aryl piperazine analogues

This invention relates to low molecular weight, non-peptidic, non-peptidomimetic, organic molecules that act as modulators of mammalian complement C5a receptors, preferably ones that act as high affinity C5a receptor ligands and also to such ligands that act as antagonists or inverse agonists of complement C5a receptors, preferably human C5a receptors, Preferred compounds of the invention possess one or more, and preferably two or more, three or more, four or more, or all of the following properties in that they are; 1) multi-aryl in structure (having a plurality of un-fused or fused aryl groups), 2) heteroaryl in structure, 3) orally available in vivo (such that a sub-lethal or preferably a pharmaceutically acceptable oral dose can provide a detectable in vitro effect such as a reduction of C5a-induced neutropenia), 4) comprised of fewer than four, preferably fewer than three, or fewer than two, or no amide bonds, and 5) capable of inhibiting leukocyte chemotaxis at nanomolar concentrations and preferably at sub-nanomolar concentrations. Specifically exemplified representative compounds include, but are not limited to optionally substituted arylimidazoles, optionally substituted arylpyridyls, optionally substituted aryl-substituted cycloalkylimidazoles, optionally substituted arylpyrazoles, optionally substituted benzimidazoles, optionally substituted aryl-substituted tetrahydroisoquinolines, and optionally substituted biaryl carboxamides. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating a variety of inflammatory and immune system disorders. Additionally, this invention relates to the use such compounds as probes for the localization of C5a receptors.

2-aminoalkylaminoquinolines as dopamine D4 ligands

Substituted imidazoles as selective modulators of Bradykinin B2 receptors

1-benzylimidazole derivatives

1-(N'-arylalkylaminoalkyl)aminoisoquinolines: a new class of dopamine receptor subtype

3-aminoalkylamino-2H-1,4-benzoxazines and 3-aminoalkylamino-2H-1,4-benzothiazines: dopamine receptor subtype specific ligands

2-(2, 3-dihydrobenzofuran-5-yl)-4-aminomethylimidazoles: dopamine receptor subtype specific ligands

1-(N&prime;-(arylalkylaminoalkyl) aminoisoquinolines; a new class of dopamine receptor subtype specific ligands

1-(N&prime;-(arylalkylaminoalkyl)) aminoisoindoles; a new class of dopamine receptor subtype specific ligands

Disclosed are compounds of the formula: ##STR1## or the pharmaceutically acceptable acid addition salts thereof, wherein:

3-aminoalkylamino-2H-1,4-benzoxazines and

Disclosed are compounds of the formula ##STR1## or the pharmaceutically acceptable salts thereof wherein the 6-membered A ring may be optionally substituted with up to four groups independently selected from halogen, hydroxy, lower alkyl, or lower alkoxy;

1-(N-(arylalkylaminoalkyl) aminoisoquinolines; a new class of dopamine

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Branford, CT, United States of America

Xiao-shu He