piperidines and piperidine-4-carboxamide

Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer's disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Butyrylcholinesterase; Cattle; Cholinesterase Inhibitors; Factor Xa; Factor Xa Inhibitors; Humans; Molecular Docking Simulation; Piperidines; Structure-Activity Relationship; Thrombin

Alzheimer's disease (AD), a common chronic neurodegenerative disease, has become a major public health concern. Despite years of research, therapeutics for AD are limited. Overexpression of secretory glutaminyl cyclase (sQC) in AD brain leads to the formation of a highly neurotoxic pyroglutamate variant of amyloid beta, pGlu-Aβ, which acts as a potential seed for the aggregation of full length Aβ. Preventing the formation of pGlu-Aβ through inhibition of sQC has become an attractive disease-modifying therapy in AD. In this current study, through a pharmacophore assisted high throughput virtual screening, we report a novel sQC inhibitor (Cpd-41) with a piperidine-4-carboxamide moiety (IC

Topics: Alzheimer Disease; Aminoacyltransferases; Amyloid beta-Peptides; Brain; Cell Line, Tumor; Humans; Molecular Docking Simulation; Piperidines; Pyrrolidonecarboxylic Acid

Topics: Animals; Antipsychotic Agents; Drug Design; Humans; Ligands; Models, Molecular; Piperidines; Receptors, G-Protein-Coupled; Schizophrenia; Structure-Activity Relationship

Starting from a weak screening hit, potent and selective inhibitors of the MALT1 protease function were elaborated. Advanced compounds displayed high potency in biochemical and cellular assays. Compounds showed activity in a mechanistic Jurkat T cell activation assay as well as in the B-cell lymphoma line OCI-Ly3, which suggests potential use of MALT1 inhibitors in the treatment of autoimmune diseases as well as B-cell lymphomas with a dysregulated NF-κB pathway. Initially, rat pharmacokinetic properties of this compound series were dominated by very high clearance which could be linked to amide cleavage. Using a rat hepatocyte assay a good in vitro-in vivo correlation could be established which led to the identification of compounds with improved PK properties.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Hepatocytes; Humans; Jurkat Cells; Microsomes; Molecular Structure; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; Piperidines; Proteolysis; Rats; Structure-Activity Relationship

Prostaglandin E2 (PGE2) is a terminal prostaglandin in the cyclooxygenase (COX) pathway. Inhibition of PGE2 production may relieve inflammatory symptoms such as fever, arthritis, and inflammatory pain. We report here the profile of a novel selective PGE2 synthesis inhibitor, compound A [N-[(1S,3S)-3-carbamoylcyclohexyl]-1-(6-methyl-3-phenylquinolin-2-yl)piperidine-4-carboxamide], in animal models of pyrexia and inflammation. The compound selectively suppressed the synthesis of PGE2 in human alveolar adenocarcinoma cell line A549 cells and rat macrophages. In the lipopolysaccharide-induced pyrexia model, this compound selectively reduced PGE2 production in cerebrospinal fluid and showed an anti-pyretic effect. In the adjuvant-induced arthritis model, compound A therapeutically decreased foot swelling in the established arthritis. Our data demonstrates that selective suppression of PGE2 synthesis shows anti-pyretic and anti-inflammatory effects, suggesting that selective PGE2 synthesis inhibitors can be applied as an alternative treatment to nonsteroidal, anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors.

Topics: A549 Cells; Animals; Anti-Inflammatory Agents; Antipyretics; Arthritis, Experimental; Cell Line, Tumor; Dinoprostone; Disease Models, Animal; Fever; Humans; Inflammation; Lipopolysaccharides; Macrophages, Peritoneal; Piperidines; Quinolines; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley

We report the design, synthesis and binding evaluation against σ1 and σ2 receptors of a series of new piperidine-4-carboxamide derivatives variously substituted on the amide nitrogen atom. Specifically, we assessed the effects exerted on σ receptor affinity by substituting the N-benzylcarboxamide group present on a series of compounds previously synthesized in our laboratory with different cyclic or linear moieties. The synthesized compounds 2a-o were tested to estimate their affinity and selectivity toward σ1 and σ2 receptors. Very high σ1 affinity (Ki = 3.7 nM) and Kiσ2/Kiσ1 selectivity ratio (351) were found for the tetrahydroquinoline derivative 2k, featuring a 4-chlorobenzyl moiety linked to the piperidine nitrogen atom.

Topics: Dose-Response Relationship, Drug; Humans; Ligands; Models, Molecular; Molecular Structure; Piperidines; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship