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Peter T Meinke

Publications and source records attributed to Peter T Meinke.

At least 19 recordsLinked to original sources
PubMed2006

A series of novel, potent, and selective histone deacetylase inhibitors.

Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in clinical trials. A structurally novel series of HDAC inhibitors based on the natural cyclic tetrapeptide Apicidin is described. Selected screening of the sample collection looking for L-2-amino-8-oxodecanoic acid (L-Aoda) derivatives identified a small acyclic lead molecule 1 with the unusual ketone zinc binding group. SAR studies around this lead resulted in optimization to potent, low molecular weight, selective, non-hydroxamic acid HDAC inhibitors, equipotent to current clinical candidates.

Amides↗
PubMed2005

Design and synthesis of potent and subtype-selective PPARalpha agonists.

Beginning with a moderately potent PPARgamma agonist 9, a series of potent and highly subtype-selective PPARalpha agonists was identified through a systematic SAR study. Based on the results of the efficacy studies in the hamster and dog models of dyslipidemia and the desired pharmacokinetic data, the optimized compound 39 was selected for further profiling.

Animals↗
PubMed2005

Novel 2,3-dihydrobenzofuran-2-carboxylic acids: highly potent and subtype-selective PPARalpha agonists with potent hypolipidemic activity.

The design and synthesis of a novel class of 2,3-dihydrobenzofuran-2-carboxylic acids as highly potent and subtype-selective PPARalpha agonists are reported. Systematic study of structure-activity relationships has identified several key structural elements within this class for maintaining the potency and subtype selectivity. Select compounds were evaluated in animal models of dyslipidemia using Syrian hamsters and male Beagle dogs, and all these compounds displayed excellent cholesterol- and triglyceride-lowering activity at dose levels that were much lower than the marketed weak PPARalpha agonist fenofibrate.

Animals↗
PubMed2005

Discovery of potent and use-dependent sodium channel blockers for treatment of chronic pain.

A new series of voltage-gated sodium channel blockers with potential for treatment of chronic pain is reported. Systematic structure-activity relationship studies, starting with compound 1, led to identification of potent analogs that displayed use-dependent block of sodium channels, were efficacious in pain models in vivo, and most importantly, were devoid of activity against the cardiac potassium channel hERG.

Chronic Disease↗
PubMed2005

Selective PPARgamma modulators with improved pharmacological profiles.

A series of metabolically robust N-benzyl-indole selective PPARgamma modulators with either a 3-benzoyl or 3-benzisoxazoyl moiety have been identified. In vitro, these compounds are partial agonists and exhibit reduced adipogenesis in human adipocytes. In vivo, these SPPARgammaMs result in potent glucose lowering in db/db mice and attenuate increases in heart weight and brown adipose tissue that is typically observed in rats upon treatment with PPARgamma full agonists.

Animals↗
PubMed2005

PPAR ligands: potential therapies for metabolic syndrome.

Metabolic syndrome (MS), a condition characterized by multiple related clinical disorders including insulin resistance, central obesity, hyperlipidemia, hypertension, and heart disease, is an increasingly prevalent disease in industrialized societies. The intense research interest in the peroxisome proliferator-activated receptors (PPARs), by both the pharmaceutical industry and academia, stems largely from the well-documented therapeutic actions of their synthetic agonists in alleviating several of the maladies associated with MS. This report focuses on the current understanding of the mechanisms of action of PPAR agents and their clinical use in the context of MS.

Cardiovascular Diseases↗
PubMed2005

PPARs: therapeutic targets for metabolic disease.

The three peroxisome-proliferator-activated receptor (PPAR) subtypes, PPAR-gamma, PPAR-alpha and PPAR-delta, are nuclear receptors that have been the focus of extensive research during the past decade. These receptors function as lipid sensors that coordinately regulate the expression of large gene arrays and, thereby, modulate important metabolic events. They are also the targets of drugs that are effective in the treatment of metabolic disorders (type 2 diabetes mellitus and atherosclerosis) that afflict industrialized societies at epidemic levels. Ongoing research indicates that modulation of PPAR activity might be an effective therapy for additional maladies associated with the metabolic syndrome, including obesity. Novel PPAR ligands are now being developed that possess broader efficacies and improved tolerability compared with currently available therapeutic agents.

Animals↗
PubMed2004

A disubstituted succinamide is a potent sodium channel blocker with efficacy in a rat pain model.

Sodium channel blockers are used clinically to treat a number of neuropathic pain conditions, but more potent and selective agents should improve on the therapeutic index of currently used drugs. In a high-throughput functional assay, a novel sodium channel (Na(V)) blocker, N-[[2'-(aminosulfonyl)biphenyl-4-yl]methyl]-N'-(2,2'-bithien-5-ylmethyl)succinamide (BPBTS), was discovered. BPBTS is 2 orders of magnitude more potent than anticonvulsant and antiarrhythmic sodium channel blockers currently used to treat neuropathic pain. Resembling block by these agents, block of Na(V)1.2, Na(V)1.5, and Na(V)1.7 by BPBTS was found to be voltage- and use-dependent. BPBTS appeared to bind preferentially to open and inactivated states and caused a dose-dependent hyperpolarizing shift in the steady-state availability curves for all sodium channel subtypes tested. The affinity of BPBTS for the resting and inactivated states of Na(V)1.2 was 1.2 and 0.14 microM, respectively. BPBTS blocked Na(V)1.7 and Na(V)1.2 with similar potency, whereas block of Na(V)1.5 was slightly more potent. The slow tetrodotoxin-resistant Na(+) current in small-diameter DRG neurons was also potently blocked by BPBTS. [(3)H]BPBTS bound with high affinity to a single class of sites present in rat brain synaptosomal membranes (K(d) = 6.1 nM), and in membranes derived from HEK cells stably expressing Na(V)1.5 (K(d) = 0.9 nM). BPBTS dose-dependently attenuated nociceptive behavior in the formalin test, a rat model of tonic pain. On the basis of these findings, BPBTS represents a structurally novel and potent sodium channel blocker that may be used as a template for the development of analgesic agents.

Amides↗
PubMed2003

Guggulsterone is a farnesoid X receptor antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump.

Guggulipid is an extract of the guggul tree Commiphora mukul and has been widely used to treat hyperlipidemia in humans. The plant sterol guggulsterone (GS) is the active agent in this extract. Recent studies have shown that GS can act as an antagonist ligand for farnesoid X receptor (FXR) and decrease expression of bile acid-activated genes. Here we show that GS, although an FXR antagonist in coactivator association assays, enhances FXR agonist-induced transcription of bile salt export pump (BSEP), a major hepatic bile acid transporter. In HepG2 cells, in the presence of an FXR agonist such as chenodeoxycholate or GW4064, GS enhanced endogenous BSEP expression with a maximum induction of 400-500% that induced by an FXR agonist alone. This enhancement was also readily observed in FXR-dependent BSEP promoter activation using a luciferase reporter construct. In addition, GS alone slightly increased BSEP promoter activation in the absence of an FXR agonist. Consistent with the results in HepG2, guggulipid treatment in Fisher rats increased BSEP mRNA. Interestingly, in these animals expression of the orphan nuclear receptor SHP (small heterodimer partner), a known FXR target, was also significantly increased, whereas expression of other FXR targets including cholesterol 7alpha-hydroxylase (Cyp 7a1), sterol 12alpha-hydroxylase (Cyp 8b1), and the intestinal bile acid-binding protein (I-BABP), remained unchanged. Thus, we propose that GS is a selective bile acid receptor modulator that regulates expression of a subset of FXR targets. Guggulipid treatment in rats lowered serum triglyceride and raised serum high density lipoprotein levels. Taken together, these data suggest that guggulsterone defines a novel class of FXR ligands characterized by antagonist activities in coactivator association assays but with the ability to enhance the action of agonists on BSEP expression in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Nodulisporic acid side-chain modifications: access to the 2", 3", 4", and 6" registers.

Efficient routes to access the 2", 3", 4", and 6" registers of the nodulisporic acid (NsA) side chain are disclosed. A mild one-carbon, Ph(2)CdoublebondNCH(2)CtriplebondN mediated homologation of NsA's 3"-aldehyde permitted access to the 4"-register. Curtius reaction of NsA's 3"-acid yielded the corresponding 2"-aldehyde 4 from which the unnatural Delta(2",3")-olefin isomer 2b was obtained. In addition, Arndt-Eistert reactions of the parent NsA permitted a one-carbon homologation to the 6" register. These efforts identified new analogues with significant flea activity and illustrated the biological significance of unsaturation at the 1",2" register.

Alkenes↗
PubMed2002

Side-chain homologation of nodulisporic acid: synthesis of potent new dienyl derivatives.

A series of new, diene-modified nodulisporic acid analogues (2) bearing diverse functionality at the 3"- and 4"-sites was efficiently prepared from the 3"-aldehyde 3. Biological evaluation of these synthetic nodulisporic acid analogues for systemic flea efficacy identified potent compounds and further clarified the structural requirements for ectoparasite activity.

Animals↗
PubMed2002

Lithocholic acid decreases expression of bile salt export pump through farnesoid X receptor antagonist activity.

Bile salt export pump (BSEP) is a major bile acid transporter in the liver. Mutations in BSEP result in progressive intrahepatic cholestasis, a severe liver disease that impairs bile flow and causes irreversible liver damage. BSEP is a target for inhibition and down-regulation by drugs and abnormal bile salt metabolites, and such inhibition and down-regulation may result in bile acid retention and intrahepatic cholestasis. In this study, we quantitatively analyzed the regulation of BSEP expression by FXR ligands in primary human hepatocytes and HepG2 cells. We demonstrate that BSEP expression is dramatically regulated by ligands of the nuclear receptor farnesoid X receptor (FXR). Both the endogenous FXR agonist chenodeoxycholate (CDCA) and synthetic FXR ligand GW4064 effectively increased BSEP mRNA in both cell types. This up-regulation was readily detectable at as early as 3 h, and the ligand potency for BSEP regulation correlates with the intrinsic activity on FXR. These results suggest BSEP as a direct target of FXR and support the recent report that the BSEP promoter is transactivated by FXR. In contrast to CDCA and GW4064, lithocholate (LCA), a hydrophobic bile acid and a potent inducer of cholestasis, strongly decreased BSEP expression. Previous studies did not identify LCA as an FXR antagonist ligand in cells, but we show here that LCA is an FXR antagonist with partial agonist activity in cells. In an in vitro co-activator association assay, LCA decreased CDCA- and GW4064-induced FXR activation with an IC(50) of 1 microm. In HepG2 cells, LCA also effectively antagonized GW4064-enhanced FXR transactivation. These data suggest that the toxic and cholestatic effect of LCA in animals may result from its down-regulation of BSEP through FXR. Taken together, these observations indicate that FXR plays an important role in BSEP gene expression and that FXR ligands may be potential therapeutic drugs for intrahepatic cholestasis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Ivermectin and nodulisporic acid receptors in Drosophila melanogaster contain both gamma-aminobutyric acid-gated Rdl and glutamate-gated GluCl alpha chloride channel subunits.

35S-labeled derivatives of the insecticides nodulisporic acid and ivermectin were synthesized and demonstrated to bind with high affinity to a population of receptors in Drosophila head membranes that were previously shown to be associated with a glutamate-gated chloride channel. Nodulisporic acid binding was modeled as binding to a single population of receptors. Ivermectin binding was composed of at least two kinetically distinct receptor populations, only one of which was associated with nodulisporic acid binding. The binding of these two ligands was modulated by glutamate, ivermectin, and antagonists of invertebrate gamma-aminobutyric acid (GABA)ergic receptors. Because solubilized nodulisporic acid and ivermectin receptors comigrated as 230-kDa complexes by gel filtration, antisera specific for both the Drosophila glutamate-gated chloride channel subunit GluCl alpha (DmGluCl alpha) and the GABA-gated chloride channel subunit Rdl (DmRdl) proteins were generated and used to examine the possible coassembly of these two subunits within a single receptor complex. DmGluCl alpha antibodies immunoprecipitated all of the ivermectin and nodulisporic acid receptors solubilized by detergent from Drosophila head membranes. DmRdl antibodies also immunoprecipitated all solubilized nodulisporic receptors, but only approximately 70% of the ivermectin receptors. These data suggest that both DmGluCl alpha and DmRdl are components of nodulisporic acid and ivermectin receptors, and that there also exists a distinct class of ivermectin receptors that contains the DmGluCl alpha subunit but not the DmRdl subunit. This co-association of DmGluCl alpha and DmRdl represents the first biochemical and immunological evidence of coassembly of subunits from two different subclasses of ligand-gated ion channel subunits.

Animals↗
PubMed2002

Photochemical preparation of a pyridone containing tetracycle: a Jak protein kinase inhibitor.

Jak3 is a protein tyrosine kinase that is associated with the shared gamma chain of receptors for cytokines IL2, IL4, IL7, IL9, and IL13. We have discovered that a pyridone-containing tetracycle (6) may be prepared from trisubstituted imidazole (5) in high yield by irradiation with >350 nm light. Compound 6 inhibits Jak3 with K(I)=5 nM; it also inhibits Jak family members Tyk2 and Jak2 with IC(50)=1 nM and murine Jak1with IC(50)=15 nM. Compound 6 was tested as an inhibitor of 21 other protein kinases; it inhibited these kinases with IC(50)s ranging from 130 nM to >10 microM. Compound 6 also blocks IL2 and IL4 dependent proliferation of CTLL cells and inhibits the phosphorylation of STAT5 (an in vivo substrate of the Jak family) as measured by Western blotting.

Animals↗
PubMed2002

Synthesis of side chain truncated 3"-aldehyde, 3"-carboxylic acid, and 1"-aldehyde from nodulisporic acid A.

An efficient synthesis of the truncated 3"-aldehyde (3) from nodulisporic acid A (1) under mild conditions is described. Further oxidation of 3 to 3"-carboxylic acid (4) and its subsequent oxidative degradation produced 1"-aldehyde (5). These new derivatives are versatile intermediates for the preparation of new, side chain modified derivatives of nodulisporic acid A. [reaction: see text]

Aldehydes↗
PubMed2002

Recent advances in the modulation of voltage-gated ion channels for the treatment of epilepsy.

Regardless of the voltage-gated ion channel that is targeted in a drug discovery effort for the treatment of epilepsy, two routes have been followed historically: 1). a compound initially, and often surreptitiously, discovered due to activity in animal seizure models is further optimized by medicinal chemistry, or 2). a molecular target is identified based on the phenotype of transgenic animals, or linkage studies from humans with the disease, and compounds are then investigated within a mechanistic framework. Antagonists of voltage-gated sodium channels have been pursued utilizing primarily the first approach; many of these compounds also have significant activity at other ion channels. Both approaches have been utilized to discover voltage-gated calcium channel antagonists, although most efforts to date have used the first approach. Several spontaneous mutant mice and transgenic animals have been utilized to probe the role of the numerous voltage-gated calcium channel subunits and their isoforms as potential molecular targets. Compounds that open or prolong the opening of voltage-gated potassium channels have been discovered using the first approach, with a detailed understanding of the molecular target and mechanism of action coming to light several years later. Genetic evidence from humans is limited to relatively rare forms of epilepsy, and transgenic animals with interesting phenotypes do not always translate into good molecular targets in humans. No clinically-useful antiepileptic drug (AED) has been developed to date that specifically interacts with one, or even one class, of ion channels to produce a therapeutic effect. The tools now exist to search for potent, selective, and safe ion channel modulators for the treatment of epilepsy. This review seeks to summarize the most recent pre-clinical and clinical efforts focused on voltage-gated ion-channels for the development of AEDs.

Animals↗