Discovery of a series of (4,5-dihydroimidazol-2-yl)-biphenylamine 5-HT7 agonists

A novel (4,5-dihydroimidazol-2-yl)-biphenylamine series of 5-HT(7) agonist compounds was developed from a structurally related lead compound 1. The newly discovered series is exemplified by compound 2 that possesses high affinity for 5-HT(7) receptors and shows intrinsic agonist activity in functional assays. This new series has significant alpha(1) and alpha(2) activities perhaps due to the presence of the 2-aminoimidazoline moiety.     

Studies on a series of potent, orally bioavailable, 5-HT(1) receptor ligands

A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.     

Design, synthesis, single-crystal and preliminary antitumor activity of novel arenesulfonylimidazolidin-2-ones

Novel series of 1-(arenesulfonyl)imidazolidin-2-one (3a-i) and 1,3-bis(arenesulfonyl)imidazolidin-2-one (5a-i) have been synthesized and tested for their antitumor activity against 60 tumor cell lines taken from nine different organs. A significant inhibition for cancer cells was observed with series 5a-i compounds compared with the series 3a-i which showed a weak inhibition. Compounds 5a-i showed good inhibitory effect at the lung cancer HOP-92 and renal cancer CAKI-1 and UO-31 cell lines. Compound 5e showed remarkable broad-spectrum antitumor activity.     

Structure-activity relationship analysis of a novel necroptosis inhibitor, Necrostatin-5

Necrostatin-5 (Nec-5) is a novel potent small-molecule inhibitor of necroptosis structurally distinct from previously described Necrostatin-1 (Nec-1), and therefore, represents a new direction for the inhibition of this cellular caspase-independent necrotic cell death mechanism. Here, we describe a series of structural modifications of Nec-5 and the structure-activity relationship (SAR) of Nec-5 series in inhibiting necroptosis.     

Proton magnetic resonance spectra of tetracyclic triterpene alcohols under the influence of a lanthanide shift reagent.

The proton magnetic resonance spectra were measured for four series of tetracyclic triterpen-3beta-ols, i.e. 5alpha-lanostane, 5alpha-euphane, 5alpha-tirucallane, and 5alpha-dammarane series, in the presence of a molar equivalent of tris (dipivalomethanato) europium, a lanthanide shift reagent. The spectral pattern measured in the presence of the shift reagent was found useful for distinguishing each series and also for characterizing each skeletal isomer of tetracyclic triterpene alcohols.     

Identification and optimisation of 5-amino-7-aryldihydro-1,4-diazepines as 5-HT2A ligands

A several series of low molecular weight 5-HT(2A) leads were identified from an analysis of HTS data, the exploration of SAR and optimization of one series using parallel synthesis are described, affording compound 22 (5-HT(2A) IC(50) 1.1 nM).     

Very-long-chain hydroxyaldehydes from the cuticular wax of Taxus baccata needles

In the cuticular wax of Taxus baccata needles, homologous series of very-long-chain 1,5-alkanediols and 5-hydroxyaldehydes were identified by various chemical transformations with product assignment using GC-MS. The 1,5-alkanediols had chain lengths ranging from C(28) to C(38), with strong predominance of even carbon numbers and a maximum at C(32) (29%). The series of 5-hydroxyaldehydes comprised chain lengths C(24) and C(26)-C(36), and showed a pronounced prevalence of even-numbered homologues. 5-Hydroxyoctacosanal was the most abundant compound of the series (42%). The 5-hydroxyaldehydes together amounted to 0.4 microg/cm(2), corresponding to 1.2% of total wax of the needles. A polyketide-like biosynthetic pathway is proposed based on the (similar) chain length distributions and functional group patterns for both compound classes.     

Conformationally rigid N-acyl-5-alkyl-L-prolyl-pyrrolidines as prolyl oligopeptidase inhibitors

In the N-acyl-L-prolyl-pyrrolidine type of prolyl oligopeptidase inhibitors the L-prolyl group was replaced by different 5-alkyl-L-prolyl groups, resulting in a series of N-acyl-5-alkyl-L-prolyl-pyrrolidines. Since N-amides of 5-alkyl-L-prolines are conformationally more rigid than those of L-proline, the main objective was to make more rigid prolyl oligopeptidase inhibitors. In the series of compounds where the N-acyl group was a Boc group, the 5(R)-tert-butyl group increased the potency strongly. A similar effect was not observed for the 5(S)-tert-butyl group. In the series of compounds where the N-acyl group was a 4-phenylbutanoyl group, the 5(R)-tert-butyl, 5(R)-methyl and 5(S)-methyl groups did not have an effect on the potency [the 5(S)-tert-butyl group was not tested in this series]. As an additional effect, the 5-tert-butyl groups increased the log P of the compounds 1.5 log units, which might be beneficial when targeting the compounds to the brain.     

Inhibition of brain nitric oxide synthesis enhances and prolongs the hypertensive effect of centrally administered interleukin-1beta in rats

The present study was designed to find out whether brain nitric oxide (NO) influences hemodynamic response to intracerebroventricular (ICV) infusion of interleukin-1 beta (IL-1beta). Mean arterial blood pressure (MAP) and heart rate (HR) were recorded in seven series of experiments performed on conscious Sprague-Dawley rats receiving during 60 min ICV infusion of: 0.9% NaCl (5 microl/h; series 1), IL-1beta (100 ng/h; series 2), NO synthase inhibitor (L-NAME, 1mg/h; series 3), IL-1beta together with L-NAME (series 4), IL-1beta together with inactive isomer of NO synthase inhibitor (D-NAME, 1mg/h; series 5), NO donor (SNAP, 40 microg/h; series 6) and IL-1beta together with SNAP (series 7). ICV infusion of saline did not influence MAP while administration of IL-1beta as well as IL-1beta together with D-NAME elicited a significant, though transient, increase in MAP. In series 4, combined infusion of IL-1beta and L-NAME exerted an increase in MAP, which persisted until the end of the experiment and was significantly higher than in series 2 and 5. In series 7, infusion of SNAP together with IL-1beta abolished the pressor effect of IL-1beta. HR was not significantly altered in any of the experimental series. These results demonstrate that inhibition of NO synthesis in the brain enhances and prolongs the pressor response to IL-1beta, whereas concomitant administration of NO donor abolishes the hemodynamic effect of IL-1beta. Therefore, we conclude that NO generated in the brain is involved in buffering the pressor response to IL-1beta.     

Studies toward the discovery of the next generation of antidepressants. Part 6: Dual 5-HT1A receptor and serotonin transporter affinity within a class of arylpiperazinyl-cyclohexyl indole derivatives

Based on the previously reported discovery lead, 3-(cis-4-(4-(1H-indol-4-yl)piperazin-1-yl)cyclohexyl)-5-fluoro-1H-indole (2), a series of related arylpiperazin-4-yl-cyclohexyl indole analogs were synthesized then evaluated as 5-HT transporter inhibitors and 5-HT(1A) receptor antagonists. The investigation of the structure-activity relationships revealed the optimal pharmacophoric elements required for activities in this series. The best example from this study, 5-(piperazin-1-yl)quinoline analog (trans-20), exhibited equal binding affinities at 5-HT transporter (K(i)=4.9nM), 5-HT(1A) receptor (K(i)=6.2nM) and functioned as a 5-HT(1A) receptor antagonist.     

Discovery and SAR of a novel series of non-MPEP site mGlu5 PAMs based on an aryl glycine sulfonamide scaffold

Herein we report the discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu₅) positive allosteric modulators (PAMs) based on an aryl glycine sulfonamide scaffold. This series represents a rare non-MPEP site mGlu₅ PAM chemotype.     

Synthesis and in vitro binding studies of substituted piperidine naphthamides. Part I: Influence of the substitution on the basic nitrogen and the position of the amide on the affinity for D2L, D4.2, and 5-HT2A receptors

A series of 1- and 2-naphthamides has been prepared and tested for in vitro binding to D(2L), D(4.2), and 5-HT(2A) receptors. Different compounds display selectivity for D(4.2) and 5-HT(2A) receptors versus D(2L) receptors. N-(1-Arylalkyl-piperidin-4-yl) carboxamides have higher affinities than the corresponding N-(4-arylalkylamino-piperidin-1-yl) carboxamide analogues. A benzyl moiety in position 1 of the piperidine in the 2-naphthamide series (2) appears to be the best choice for a favorable interaction with D(4.2) and 5-HT(2A) receptors. Increasing the linker length between the phenyl ring and the basic nitrogen led to a decreased affinity for these receptors. In the 1-naphthamide series, the most potent D(4.2) ligand (7) possesses a phenylpropyl moiety while its affinity for 5-HT(2A) receptors is strongly reduced. All compounds with significant affinity for D(4.2) and 5-HT(2A) receptors were antagonists.     

Thiazoles and thiopyridines: novel series of high affinity h5HT(7) ligands

A series of thiazole based 5HT(7) ligands has been identified from screening. Optimisation of the pendent aryl group and modification of the core gave a related series of high affinity, selective thiopyridine based 5HT(7) ligands, the most active of which behaves as a partial agonist.     

Design, synthesis and preliminary screening of novel 3-(2-N,N-dimethylaminoethylthio) indole derivatives as potential 5-HT(6) receptor ligands

The synthesis and potential 5-hydroxytryptamine(6) receptor (5-HT6R) antagonist activity of a novel series of N-arylsulfonyl-3-(2-N,N-dimethylaminoethylthio) indoles has been reported. The molecular modeling, synthesis and in-vitro radioligand binding data of this series are discussed. The present article describes 37 derivatives of the title series. It was observed that the increased side-chain length with the insertion of a sulfur atom did not lead to the loss of binding affinity of these compounds, although the affinities were reduced. The compounds exhibited moderate affinity and selectivity to human 5-HT6 receptors.     

Efficacy switching SAR of mGluR5 allosteric modulators: highly potent positive and negative modulators from one chemotype

A series of metabotropic glutamate 5 receptor (mGluR5) allosteric ligands with positive, negative or no modulatory efficacy is described. The ability of this series to yield both mGluR5 PAMs and NAMs with single-digit nanomolar potency is unusual, and the underlying SAR is detailed.     

5-Phenyl substituted 1-methyl-2-pyridones and 4'-substituted biphenyl-4-carboxylic acids. synthesis and evaluation as inhibitors of steroid-5alpha-reductase type 1 and 2.

The synthesis of a series of 5-phenyl substituted 1-methyl-2-pyridones (I) and 4'-substituted biphenyl-4-carboxylic acids (II) as novel A-C ring steroidomimetic inhibitors of 5alpha-reductase (5alphaR) is described. Compounds 1-4 (I) were synthesized by palladium catalyzed cross coupling (Ishikura) reaction between diethyl(3-pyridyl)borane and aryl halides (1b-4b) followed by alpha-oxidation with sodium ferrocyanate of the 1-methyl-pyridinium salt. Inhibitors II (5-18) were obtained either by two successive Friedel-Crafts acylations from biphenyl (5a-10a) followed by saponification to yield the corresponding carboxylic acids (5-10) or by Suzuki cross coupling reaction to give the 4'-substituted biphenyl-4-carbaldehydes 11a-18a. The latter compounds were subjected to a Lindgren oxidation to yield compounds 11-18. The compounds were tested for inhibitory activity toward human and rat 5alphaR1 and 2. The test compounds inhibited 5alphaR, showing a broad range of inhibitory potencies. The best compound in series I was the N-(dicyclohexyl)-4-(1,2-dihydro-1-methyl-2-oxopyrid-5-yl)benzamide 4 exhibiting an IC(50) value for the human type 2 enzyme of 10 microM. In series II, the most active compound toward human type 2 isozyme was the 4'-(dicyclohexyl)acetyl-4-biphenyl carboxylic acid (10; IC(50)=220nM). Both series showed only marginal activity toward the human type 1 isozyme. In conclusion, the biphenyl carboxylic acids (II) are more appropriate for 5alphaR inhibition than the 5-phenyl-1-methyl-2-pyridones (I). Especially the 4'-carbonyl compounds 5-10 represent new lead structures for the development of novel human type 2 inhibitors.     

Synthesis and anti-inflammatory activity of some 3-(4,6-disubtituted-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl) propanoic acid derivatives

A series of 3-(4,6-disubtituted-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl) propanoic acid derivatives has been synthesized by condensation of thiourea, 5-(4-subtituted phenyl)-5-oxopentanoic acid and substituted aldehyde. The synthesized compounds were screened for their anti-inflammatory activity using rat paw edema method. Most of the compounds from the series showed significant (p <0.05) anti-inflammatory activity.     

CCR5 receptor antagonists: discovery and SAR study of guanylhydrazone derivatives

High throughput screening (HTS) led to the identification of the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde as a CCR5 receptor antagonist. Initial modifications of the guanylhydrazone series indicated that substitution of the benzyl group at the para-position was well tolerated. Substitution at the 5-position of the central phenyl ring was critical for potency. Replacement of the guanylhydrazone group led to the discovery of a novel series of CCR5 antagonists.     

Inhibitors of phenylalanine ammonia-lyase (PAL): synthesis and biological evaluation of 5-substituted 2-aminoindane-2-phosphonic acids

A series of 5-substituted derivatives of the potent phenylalanine ammonia-lyase (PAL) inhibitor 2-aminoindane-2-phosphonic acid (AIP; 2) were synthesized. The AIP analogues 3-7, with additional NO2, NH2, Me, Br, and OH groups, respectively, were tested as in vitro inhibitors of buckwheat PAL, and as in vivo inhibitors of anthocyanin biosynthesis. Within this series, the racemic 5-bromo (6) and 5-methyl (7) congeners were biologically most active (Table), although being ca. one order of magnitude less potent than AIP proper.