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At least 127 records · Page 7Linked to original sources
PubMed2004

Gamma-amino-substituted analogues of 1-[(S)-2,4-diaminobutanoyl]piperidine as highly potent and selective dipeptidyl peptidase II inhibitors.

Using 1-[(S)-2,4-diaminobutanoyl]piperidine as lead compound, we developed a large series of highly potent and selective dipeptidyl peptidase II (DPP II) inhibitors. gamma-Amino substitution with arylalkyl groups, for example, a 2-chlorobenzyl moiety, resulted in a DPP II inhibitor with an IC(50) = 0.23 nM and a high selectivity toward DPP IV (IC(50) = 345 microM). Furthermore, it was shown that the basicity of the gamma-amino is important and that alpha-amino substitution is not favorable. Piperidine-2-nitriles did not show an increase in potency but rather reduced the selectivity. Introduction of a 4-methyl or a 3-fluorine on piperidine improved selectivity and preserved the high potency.

Dipeptidyl Peptidase 4↗
PubMed2006

Discovery of a piperidine-4-carboxamide CCR5 antagonist (TAK-220) with highly potent Anti-HIV-1 activity.

We incorporated various polar groups into previously described piperidine-4-carboxamide CCR5 antagonists to improve their metabolic stability in human hepatic microsomes. Introducing a carbamoyl group into the phenyl ring of the 4-benzylpiperidine moiety afforded the less lipophilic compound 5f, which possessed both high metabolic stability and good inhibitory activity of HIV-1 envelope-mediated membrane fusion (IC(50) = 5.8 nM). Further optimization to increase potency led to the discovery of 1-acetyl-N-{3-[4-(4-carbamoylbenzyl)piperidin-1-yl]propyl}-N-(3-chloro-4-methylphenyl)piperidine-4-carboxamide (5m, TAK-220), which showed high CCR5 binding affinity (IC(50) = 3.5 nM) and potent inhibition of membrane fusion (IC(50) = 0.42 nM), as well as good metabolic stability. Compound 5m strongly inhibited the replication of CCR5-using HIV-1 clinical isolates in human peripheral blood mononuclear cells (mean EC(50) = 1.1 nM, EC(90) = 13 nM) and exhibited a good pharmacokinetic profile in monkeys (BA = 29%). This compound has been chosen as a clinical candidate for further development.

Animals↗
PubMed2006

Elucidation of the bioactive conformation of the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of mu-opioid receptor antagonists.

The series of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have been widely investigated as opioid receptor antagonists. One of our research goals was to explore the bioactive conformation of the N-phenethyl trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine derivative 3, prototypical mu-opioid antagonist in this series. In this effort, the rotational degrees of freedom of the N-substituent of 3 were limited by incorporation of an ethylene bridge between the piperidine 2- or 6-position of 3 and the benzylic position of the N-phenethyl moiety. The overall modification led to a novel series of fused bicyclic derivatives of the octahydroquinolizine chemical class, conformationally restricted analogue of 3. The constrained analogues 6 and 9 showed high affinity toward the mu-opioid receptor. Compound 6 was found to be a mu-opioid antagonist, whereas the constrained analogue 9 displayed potent mu-agonist activity in vitro. This study provides additional information about the molecular determinants for mu recognition, the structural features affecting ligand binding, and the structure function relationships.

Animals↗
PubMed1998

Identification of an opioid kappa receptor subtype-selective N-substituent for (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine.

A three-component library of compounds was prepared in parallel using multiple simultaneous solution-phase synthetic methodology. The compounds were biased toward opioid receptor antagonist activity by incorporating (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (a potent, nonselective opioid pure antagonist) as one of the monomers. The other two monomers, which included N-substituted or unsubstituted Boc-protected amino acids and a range of substituted aryl carboxylic acids, were selected to add chemical diversity. Screening of these compounds in competitive binding experiments with the kappa opioid receptor selective ligand [3H]U69,593 led to the discovery of a novel kappa opioid receptor selective ligand, N-¿(2'S)-[3-(4-hydroxyphenyl)propanamido]-3'-methylbutyl¿-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (8, RTI-5989-29). Additional structure-activity relationship studies suggested that 8 possesses lipophilic and hydrogen-bonding sites that are important to its opioid receptor potency and selectivity. These sites appear to exist predominantly within the kappa receptor since the selectivity arises from a 530-fold loss of affinity of 8 for the mu receptor and an 18-fold increase in affinity for the kappa receptor relative to the mu-selective ligand, (+)-N-[trans-4-phenyl-2-butenyl]-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (5a). The degree of selectivity observed in the radioligand binding experiments was not observed in the functional assay. According to its ability to inhibit agonist stimulated binding of [35S]GTPgammaS at all three opioid receptors, compound 8 behaves as a mu/kappa opioid receptor pure antagonist with negligible affinity for the delta receptor.

Animals↗
PubMed1999

Fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperazin-1-yl)propyl)indoles gives selective human 5-HT1D receptor ligands with improved pharmacokinetic profiles.

It has previously been reported that a 3-(3-(piperazin-1-yl)propyl)indole series of 5-HT1D receptor ligands have pharmacokinetic advantages over the corresponding 3-(3-(piperidin-1-yl)propyl)indole series and that the reduced pKa of the piperazines compared to the piperidines may be one possible explanation for these differences. To investigate this proposal we have developed versatile synthetic strategies for the incorporation of fluorine into these ligands, producing novel series of 4-fluoropiperidines, 3-fluoro-4-aminopiperidines, and both piperazine and piperidine derivatives with one or two fluorines in the propyl linker. Ligands were identified which maintained high affinity and selectivity for the 5-HT1D receptor and showed agonist efficacy in vitro. The incorporation of fluorine was found to significantly reduce the pKa of the compounds, and this reduction of basicity was shown to have a dramatic, beneficial influence on oral absorption, although the effect on oral bioavailability could not always be accurately predicted.

Administration, Oral↗
PubMed2000

A convenient new route to piperidines, pyrrolizidines, indolizidines, and quinolizidines by cyclization of acetylenic sulfones with beta and gamma-chloroamines. Enantioselective total synthesis of indolizidines (-)-167B, (-)-209D, (-)-209B, and (-)-207A.

The methyl esters of (L)-phenylalanine and (L)-methionine underwent conjugate additions via their free amino groups to 1-(p-toluenesulfonyl)hexyne, followed by intramolecular acylation of the corresponding enamide anions and tautomerization to afford 2-benzyl-5-n-butyl-3-hydroxy-4-(p-toluenesulfonyl)pyrrole and 5-n-butyl-3-hydroxy-2-(2-methylthioethyl)-4-(p-toluenesulfonyl)pyr role, respectively. The conjugate additions of a series of acyclic and cyclic secondary beta- and gamma-chloroamines to acetylenic sulfones proceeded similarly under mild conditions. The resulting adducts were deprotonated with LDA in THF at -78 degrees C, and the resulting sulfone-stabilized carbanions underwent intramolecular alkylation to afford cyclic enamine sulfones. Thus, acyclic gamma-chloroalkyl-benzylamines afforded the corresponding 2- or 2,6-disubstituted piperidines, while 2-(chloromethyl)pyrrolidines, 2-(2-chloroethyl)pyrrolidines, 2-(chloromethyl)piperidines, and 2-(2-chloroethyl)piperidines produced the corresponding 3-substituted pyrrolizidines, 5- or 3-substituted indolizidines, and 4-substituted quinolizidines, respectively. 8-Methyl-5-substituted indolizidines were also prepared from the appropriate methyl-substituted chloroamine precursor. Enantioselective syntheses were achieved by employing chiral chloroamines derived from amino acids or other enantiopure precursors. Further transformations of several of the products provided concise syntheses of four dendrobatid alkaloids. Thus, reduction of (8aS)-5-n-propyl-6-(p-toluenesulfonyl)-delta5,6-indolizidine with sodium cyanoborohydride in trifluoroacetic acid, followed by reductive desulfonylation, afforded (-)-indolizidine 167B. The corresponding 5-n-hexyl derivative similarly produced (-)-indolizidine 209D, while (-)-(8R, 8aS)-8-methyl-5-n-pentyl-6-(p-toluenesulfonyl)-delta5,6-indo lizidine furnished (-)-indolizidine 209B. Finally, the similar reduction and debenzylation of (-)-(8R,8aS)-5-(2-benzyloxyethyl)-8-methyl-6-(p-toluenesulfo nyl)-delta5,6-indolizidine produced the corresponding 5-hydroxyethyl indolizidine. This was subjected to chlorination of the alcohol group with thionyl chloride and substitution with a higher order allyl cuprate reagent to afford (-)-indolizidine 207A.

Acylation↗
PubMed2003

Development of a [3+3] cycloaddition strategy toward functionalized piperidines.

This paper describes a novel route to functionalized piperidines via a formal [3+3] cycloaddition reaction of activated aziridines and palladium-trimethylenemethane (Pd-TMM) complexes. The cycloaddition reaction generally proceeds enantiospecifically with ring opening at the least hindered site of the aziridine. Therefore, readily available enantiomerically pure 2-substituted aziridines can be utilized to prepare enantiomerically pure 2-substituted piperidines in good to excellent yield. The N-substituent on the aziridine proved to be crucial to the success of this reaction with only 4-toluenesulfonyl (Ts) and 4-methoxybenzenesulfonyl (PMBS) aziridines permitting smooth cycloaddition to take place. Additionally, spirocyclic aziridines have been found to participate in the [3+3] cycloaddition reaction, whereas 2,3-disubstituted aziridines can be applied to provide fused bicyclic piperidines, albeit in low yield.

Aziridines↗
PubMed2005

Development of a flexible approach to Nuphar alkaloids via two enantiospecific piperidine-forming reactions.

In this paper we describe the stereoselective synthesis of functionalized lactam 7 via two enantiospecific piperidine-forming techniques and its employment in a general synthetic approach to Nuphar alkaloids. Specifically, the formation of piperidine 18 by formal [3 + 3] cycloaddition and stepwise annelation processes is described; the latter technique was found to be significantly more efficient than the Pd-catalyzed TMM addition process. Finally, exploitation of the exocyclic alkene installed in the piperidine-forming reaction in the transformation of 18 to (-)-deoxynupharidine ((-)-2), (-)-castoramine ((-)-3), and (-)-nupharolutine ((-)-4) via intermediate lactam 7 is delineated.

Alkaloids↗
PubMed2006

Access to piperidine imino-C-glycosides via stereoselective thiazole-based aminohomologation of pyranoses.

The access to piperidine homoazasugars (dideoxyiminoheptitols) from pyranoses via formal one-carbon chain elongation and exchange of the ring oxygen with the NH group is described. The key process involves the stereoselective addition of 2-thiazolylmagnesium bromide to an N-glycosylhydroxylamine, i.e., a hidden open-chain sugar nitrone. The N-thiazolylalkylhydroxylamine formed in this way is reduced to amine, and this transformed into a substituted piperidine via intramolecular cyclization by an S(N)2 process. Cleavage of the thiazole residue attached to C2 of the piperidine ring reveals the formyl group, and this is reduced to hydroxymethyl to give the target homoazasugar. A collection of six stereodiversified compounds with free OH and NH groups and isolated as hydrochlorides has been prepared.

Amines↗
PubMed2006

Divergent asymmetric synthesis of 3,5-disubstituted piperidines.

A divergent synthesis of various 3,5-dioxygenated piperidines with interesting pharmacological properties is described. A mixture of the achiral cis- and racemic trans-3,5-piperidine diol could be efficiently obtained from N-benzylglycinate in five steps by the use of chemoenzymatic methods. In the subsequent enzyme- and Ru-catalyzed reaction, the rac/meso diol mixture was efficiently transformed to the cis-(3R,5S)-diacetate with excellent diastereoselectivity and in high yield. Further transformations of the cis-diacetate selectively delivered the cis-piperidine diol and the cis-(3R,5S)-hydroxy acetate. Alternatively, the DYKAT could be stopped at the monoacetate stage to give the trans-(3R,5R)-hydroxy acetate.

Acetates↗
PubMed2002

Preformulation approaches to improve the oral bioavailability of two novel piperidine renin inhibitors in dog.

Different experimental formulations based on aqueous and oily systems, water miscible solvents, and solid dispersions were investigated for their potential to increase the oral bioavailability (F) of two novel piperidine renin inhibitors (Ro-X1: (R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]- 5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol; Ro-X2: (R)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4- methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol) in dogs compared to their administration as acidic aqueous solution. The compounds were characterized by a low solubility at pH 7 (Ro-X1: 3 micrograms/ml, Ro-X2: 24 micrograms/ml) and a high lipophilicity (Ro-X1: LogP = 5.7, Ro-X2: LogP = 3.7). For Ro-X1 oil-based vehicles resulted in an improvement in the oral bioavailability compared to the aqueous solution (F = 6 +/- 1.2%) with the best result being achieved with a solution in Capmul (F = 14.6 +/- 3.5%). By contrast, for Ro-X2 the highest bioavailability (F = 27.1 +/- 8.4%) was achieved using an aqueous solution. Computer simulations based on the physicochemical parameters of the compounds only predicted that the fraction of compound absorbed in man should be almost quantitative for Ro-X2 and only about 28% for Ro-X1. These results suggest that other factors such as extensive gut and/or hepatic metabolism as well as exclusion by intestinal transporters such as p-glycoprotein, rather than incomplete solubilization in the gut, are the major reasons for the limited oral bioavailability of both compounds.

Animals↗
PubMed1981

Mass fragmentographic analysis of piperidine levels in tissues of rats during development.

Piperidine levels in the brain and adrenal gland of rats during development were determined by mass fragmentography with deuterium-labeled piperidine as an internal standard. The levels in both organs showed distinct developmental changes, and two peaks were observed in association with the development of each organ. The initial peaks appeared in the early stage of development, that is, at the 19th day of gestation for the brain and 1 week after birth for the adrenal gland. The second peaks appeared at the age of sexual maturation (10 weeks after birth). The significance of the finding is discussed with respect to a presumed role of piperidine as a neuroendocrine modulator.

Adrenal Glands↗
PubMed2000

New strong fibrates with piperidine moiety.

New fibrates containing piperidine, 4-hydroxypiperidine, piperidin-3-ene, and piperazine moieties in the structures were synthesized and evaluated. Among the synthesized compounds, 2-[3-[1-(4-fluorobenzoyl)-piperidin-4yl]phenoxyl-2-methylpropanoic acid (9aA: AHL-157) showed very superior activities in decreasing triglyceride, cholesterol, and blood sugar compared to bezafibrate in mice and rats.

Animals↗
PubMed1975

Characterization of neuromuscular blocking action of piperidine derivatives.

cis and trans forms of 2-methyl-6-n-undecyl piperidines (C-11) are the main constituents of fire ant venom and have been studied for their mechanism of action on the neuromuscular transmission of the nerve-sartorius muscle preparation of frogs. At low concentrations (l times 10(-6)-2 times 10(-5) M), cis- and trans-C-11 irreversibly decreased the amplitude of spontaneous miniature end-plate potentials nerve-evoked end-plate potentials and iontophoretically induced acetylcholine depolarizations without changing the membrane potential. The quantal content and the focally recorded action potentials of nerve terminals remain unchanged. It was concluded that the piperidine derivatives block neuromuscular transmission postsynaptically through a decrease in the sensitivity of the end-plate membrane to acetylcholine. Pretreatment of the end-plate with d-tubocurarine did not effect the blocking action of trans-C-11. In direct binding experiments, trans-C-11 did not compete for the sites occupied by alpha-bungarotoxin, decamethonium, carbamylcholine and d-tubocurarine. These data suggest that trans-C-11 does not bind to the acetylcholine receptor site where the other cholinergic ligands have their affinity. It appears that these piperidine derivatives interfere with the coupling mechanism between acetylcholine-receptor binding and ionic conductance increases.

Acetylcholine↗
PubMed1989

Biological N-oxidation of piperidine in vitro.

The biological N-oxidation of piperidine, a pharmacologically active biogenic amine of mammals and human beings, was studied in vitro. After incubation of piperidine-HCl in a fortified rat liver microsomal preparation (9000 x g supernatant) at 37 degrees C for 30 min, 2 metabolites were detected. They were identified as N-hydroxy piperidine and 2, 3, 4, 5-tetrahydro-pyridine-1-oxide as evidenced by TLC, GLC, HPLC, GC-MS and MS.

Animals↗
PubMed1989

[Piperidine in the brain: its neurobiological significance].

Piperidine (Pip) is a normal constituent in mammalian brain, affects synaptic mechanism in the CNS, and influences neural mechanisms governing regulation of emotional behavior and extrapyramidal function. In addition, there are enzyme systems within the brain that synthesize and metabolize Pip, and uptake and storage mechanisms for Pip are found in the nerve endings. Pip is highly concentrated in the pituitary and pineal glands, hippocampus and caudate nucleus among the regions of the brain. Levels of Pip in the brain show physiological variations associated with environmental changes. The levels increase significantly under deep anesthesia. The study on the time relations of the change in brain levels of Pip and the anesthetic activity demonstrates that the level increases prior to the loss of the righting reflex and that the elevated level declines prior to the reappearance of the reflex. Furthermore, Pip levels in the lower brainstem reticular formation show sleep-related changes during REM sleep deprivation and REM sleep rebound that followed. Direct administration of Pip into the hippocampus and amygdala of cats with chronically implanted electrodes and a cannula caused resting and calmness in small doses, and seizure discharge accompanied by hyperemotionality in large doses. Administration into the pontine reticular formation induced REM and NREM sleep. Iontophoretic application produced the excitation and inhibition of single neuron activities in the cerebral cortex, hippocampus, caudate nucleus, cerebellum, and pituitary in anesthetized rats. With no anesthesia, Pip caused the inhibitory action in a higher percentage of the neurons studied, compared with the result obtained under anesthesia. Pip-induced excitation and inhibiton were blocked by tetramethylammonium but little affected by scopolamine. The kinetic study of Pip-induced Cl- current in internally perfused neurons of Aplysia, by using the 'concentration camp' and voltage clamp techniques, revealed that Pip acted on at least two components of nicotinic receptor-Cl- channel complex, and further that Pip could discriminate between the transient and the persistent components of ACh-induced Cl- current. These findings suggest that Pip may have close connections with neuroendocrine as well as neuronal functions, and further, with the mechanisms underlying sleep-consciousness and emotional function. Because of piperidine's multiplex pharmacological activities, the study of piperidine may provide a clue to the discovery of new active drugs and to the elucidation of causes of pathological states relating to the brain function.

Anesthesia↗
PubMedDate not supplied

The metabolism of roxatidine acetate hydrochloride. Liberation of deuterium from the piperidine ring during hydroxylation.

The metabolism of roxatidine acetate hydrochloride (RA), a new histamine-2 receptor antagonist, was studied by GC/MS in rats and dogs in vivo. The co-administration of 14C-RA and RA-d10 labeled with deuterium in the piperidine ring expedited the isolation and identification of 15 urinary metabolites. The major metabolites in both animals were M-1, M-8, M-10, and M-11; M-4 could be found only in the rat. The aromatic and piperidine ring-hydroxylated metabolites were found in small amounts in both species. Following the administration of RA-d10 to rats and dogs, oxygenated metabolites on the piperidine ring, such as M-3 and M-4, were isolated and their analysis indicated the unexpected loss of three or four deuterium atoms from the ring. Also, first and second isotope effects were observed on the conversion rate in vivo and retention time in HPLC, respectively.

Administration, Oral↗
PubMed2002

Stereoelectronic substituent effects in polyhydroxylated piperidines and hexahydropyridazines.

From the pK(a) values of the conjugate acids of a large series of hydroxylated piperidines and hexahydropyridazines, a consistent difference in basicity was found between stereoisomers having an axial or equatorial hydroxyl (OH) group either beta or gamma to the amine. Compounds with an equatorial OH group in the 3-position were 0.8 pH units more acidic than otherwise identical compounds with an axial OH group, whilst compounds with an equatorial OH group in the 4-position relative to the amine were 0.4 pH units more acidic than the corresponding compound with an axial OH. A similar effect was observed for the COOMe substituent. The difference in electron-withdrawing power of axial and equatorial substituents was explained by a difference in charge-dipole interactions in the two systems. Since this stereoelectronic substituent effect causes differences in basicity in different conformers, certain piperidines and hexahydropyridazines were found to change conformation upon protonation. A method for predicting the pK(a) of piperidines which takes stereochemistry into account is described.

Journal Article↗