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Overview

Previously, a novel series of 1H-4-substituted imidazole compounds were described as potent and selective histamine (HA) H3 receptor ligands (Yates et al., 1999). The present studies extend the structure-activity relationships for optimal HA H3 receptor affinity and central nervous system penetration by incorporation of a conformationally restricted cyclopropane nucleus. Moreover, the current studies extend our understanding of ligand-receptor interactions at the HA H3 receptor with the development of high affinity HA H3 receptor antagonists containing a stereochemical presentation. Structure-activity relationships were established from in vitro HA H3 receptor-binding affinities using [3H]Nalpha-methylhistamine and rat cortical tissue homogenates. Systematic optimization of multiple structural features critical for HA H3 receptor affinity provided some of the most potent HA H3 receptor agents described. For example, GT-2331 was determined to bind to a single population of HA H3 receptors with a Ki of 0.125 nM. In vivo, GT-2331 has a favorable central nervous system penetration profile with an ED50 of 0.08 mg/kg (i.p.) in rats and a long duration of action (T1/2 > 4 h). In addition, GT-2331 was extremely selective for the HA H3 receptor versus other HA receptors and a battery of neurotransmitter, neuropeptide, hormone, or enzyme systems. Several compounds were tested in vitro which suggested HA H3 receptor heterogeneity and are discussed in terms of structure-activity relationships for the HA H3 receptor.

01 May 1999·The Journal of pharmacology and experimental therapeutics

Identification and pharmacological characterization of a series of new 1H-4-substituted-imidazoyl histamine H3 receptor ligands.

Article

Author: Khan, M A ; Pawlowski, G P ; Gregory, R ; Fadnis, L ; Ali, S M ; Yates, S L ; Phillips, J G ; Tedford, C E

A new series of 1H-4-substituted imidazole compounds were synthesized and identified as potent and selective histamine (HA) H3 receptor ligands. These ligands establish that HA H3 antagonists exhibit stereoselective and conformational preferences in their binding to the HA H3 receptor. Structure-activity relationships were determined in vitro by HA H3 receptor-binding affinities using [3H]Nalpha-methylhistamine and rat cerebral cortical tissue homogenates. Several derivatives containing olefin, amide, and acetylene functional groups were identified as potent HA H3 receptor ligands. In the olefin series, GT-2227 (4-(6-cyclohexylhex-cis-3-enyl)imidazole) was identified as a potent HA H3 receptor ligand with a Ki of 4.2 +/- 0.6 nM, while the trans isomer (GT-2228) displayed a reduced potency (Ki = 15.2 +/- 2.4 nM). GT-2227 was also found to have excellent central nervous system penetration in an ex vivo binding paradigm (ED50 = 0.7 mg/kg i.p.). In the acetylene series, GT-2260 and GT-2286 both exhibited high affinity (Ki = 2.9 +/- 0.2 and 0.95 +/- 0.3 nM) and excellent central nervous system penetration profiles (ED50 = 0.43 and 0.48 mg/kg i.p., respectively). As a prototype for the series, GT-2227 showed high affinity for the human HA H3 receptor (3.2 nM) and minimal affinity for the human HA H1 (Ki = 13,407 +/- 540 nM) and H2 (Ki = 4,469 +/- 564 nM) receptor subtypes. GT-2227 also showed good selectivity for the HA H3 receptor over a broad spectrum of other neurotransmitter receptors (IC50 >/= 1 microM). Furthermore, GT-2227 improved acquisition in a cognitive paradigm without behavioral excitation or effect on spontaneous locomotor activity. In summary, the present studies demonstrate the development of novel HA H3-selective ligands, and lend support for the use of such agents in the treatment of disorders associated with cognitive or attentional deficits.

01 Jan 1999·Methods in EnzymologyQ4 · BIOLOGY

[46] Inflammatory responses to amyloid fibrils

Q4 · BIOLOGY

Article

Author: Yates, Stephen L. ; Brunden, Kurt R. ; Embury, Paula ; Kocsis-Angle, June

Our laboratory has routinely used the methodologies described here to characterize the effects of fibrillar A beta and amylin on cytokine synthesis and secretion by LPS-differentiated THP-1 cells. Because LPS-treated THP-1 cells resemble macrophage and microglia, this assay system represents an in vitro model of the potential interactions between A beta-containing senile plaques and microglia in the AD brain. As such, these methodologies should prove useful in the identification of compounds that inhibit this A beta-induced inflammatory response.

100 Deals associated with Gliatech, Inc.

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100 Translational Medicine associated with Gliatech, Inc.

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Pipeline

Pipeline Snapshot as of 27 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

GT-3001	Alzheimer Disease More	Discontinued
GT-4011	Alzheimer Disease More	Discontinued
GT-5140 ( H3 receptor )	Sleep Initiation and Maintenance Disorders More	Discontinued
GT-2016 ( H3 receptor )	Alzheimer Disease More	Discontinued
GT-2227 ( H3 receptor )	Attention Deficit Disorder With Hyperactivity More	Discontinued