Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 ...positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγ
S binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca
mobilization assay. SAR218645 potentiated mGluR2 agonist-induced contralateral turning. When SAR218645 was tested in models of the positive symptoms of schizophrenia, it reduced head twitch behavior induced by DOI, but it failed to inhibit conditioned avoidance and hyperactivity using pharmacological and transgenic models. Results from experiments in models of the cognitive symptoms associated with schizophrenia showed that SAR218645 improved MK-801-induced episodic memory deficits in rats and attenuated working memory impairment in NMDA Nr1
mice. The drug reversed disrupted latent inhibition and auditory-evoked potential in mice and rats, respectively, two endophenotypes of schizophrenia. This profile positions SAR218645 as a promising candidate for the treatment of cognitive symptoms of patients with schizophrenia, in particular those with abnormal attention and sensory gating abilities.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A novel series of histamine H
3 receptor antagonists based on the 4-(1
H-imidazol-4-yl)methylpiperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified
A novel ...series of histamine H
3 receptor antagonists based on the 4-(1
H-imidazol-4-yl)methylpiperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A series of azetidinone cholesterol absorption inhibitors related to SCH 48461 ((−)-6) has been prepared, and compounds were evaluated for their ability to inhibit hepatic cholesteryl ester formation ...in a cholesterol-fed hamster model. Although originally designed as acyl CoA:cholesterol acyltransferase (ACAT) inhibitors, comparison of in vivo potency with in vitro activity in a microsomal ACAT assay indicates no correlation between activity in these two models. The molecular mechanism by which these compounds inhibit cholesterol absorption is unknown. Despite this limitation, examination of the in vivo activity of a range of compounds has revealed clear structure−activity relationships consistent with a well-defined molecular target. The details of these structure−activity relationships and their implications on the nature of the putative pharmacophore are discussed.
A novel series of histamine H3 receptor antagonists based on the 4-(1H-imidazol-4-yl)methylpiperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural ...features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The asymmetric synthesis of a glucuronide conjugate of the 2-azetidinone cholesterol absorption inhibitor Sch 48461 was accomplished to confirm the structure of a metabolite isolated from in vivo ...sources. Key features of this article include the asymmetric synthesis of 2-azetidinones by Evan's chiral oxazolidinone methodology and glucuronide formation by a Mitsunobu protocol.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We report the discovery of novel histamine H
3 receptor antagonists based on 4-(1
H-imidazol-4-yl)methylpiperidine. The most potent compounds in the series (e.g.,
7) result from the attachment of a ...substituted aniline amide to the main pharmacophore piperidine via a two-methylene linker
We report the discovery of novel histamine H
3 receptor antagonists based on 4-(1
H-imidazol-4-yl)methylpiperidine. The most potent compounds in the series (e.g.,
7) result from the attachment of a substituted aniline amide to the main pharmacophore piperidine via a two-methylene linker.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
SAR studies directed towards the optimization of 2-azetidinone cholesterol absorption inhibitors led to the discovery of 11a, the most potent cholesterol absorption inhibitor yet identified.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We report the discovery of novel histamine H(3) receptor antagonists based on 4-(1H-imidazol-4-yl)methylpiperidine. The most potent compounds in the series (e.g., 7) result from the attachment of a ...substituted aniline amide to the main pharmacophore piperidine via a two-methylene linker.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A novel series of histamine H sub(3) receptor antagonists based on the 4- (1H-imidazol-4-yl)methylpiperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. ...Structural features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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