Synthesis and histamine H3 receptor activity of 4-(n-alkyl)-1H-imidazoles and 4-(omega-phenylalkyl)-1H-imidazoles

The influence of lipophilic moieties attached to a 4-1H-imidazole ring on the histamine H₃ receptor activity was systematically investigated. Series of 4-(n-alkyl)-1H-imidazoles and 4-(ω-phenylalkyl)-1H-imidazoles were prepared, with an alkyl chain varying from 2–9 methylene groups and from 1–9 methylene groups, respectively. The compounds were tested for their activity on the H₃ receptor under in vitro conditions. For the 4-(n-alkyl)-1H-imidazoles the activity is proportional to chain length, ranging from a pA₂ value of 6.3±0.2 for 4-(n-propyl)-1H-imidazole to a pA₂ value of 7.2±0.1 for 4-(n-decyl)-1H-imidazole. For the series 4-(ω-phenylalkyl)-4H-imidazoles an optimum in H₃ activity was found for the pentylene spacer: 4-(ω-phenylpentyl)-1H-imidazole has a pA₂ value of 7.8±0.1.     

Synthesis and in vitro antimycobacterial activity of novel 3-(1H-pyrrol-1-yl)-2-oxazolidinone analogues of PNU-100480

Pursuing our search program for new antitubercular drugs we decided to explore the potentiality of oxazolidinone moiety by synthesizing novel 3-(1H-pyrrol-1-yl)-2-oxazolidinone analogues of PNU-100480. The new derivatives were tested against atypical mycobacteria as well as against drug resistant Mycobacterium tuberculosis and some of them exhibited a fairly good activity against Mycobacterium avium complex (MAC).     

C(17,20)-lyase inhibitors. Part 2: design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C(17,20)-lyase inhibitors

A series of 1- and 4-(2-naphthylmethyl)-1H-imidazoles (3 and 4) has been synthesized and evaluated as C(17,20)-lyase inhibitors. Several 6-methoxynaphthyl derivatives showed potent C(17,20)-lyase inhibition, suppression of testosterone biosynthesis in rats and reduction in the weight of prostate and seminal vesicles in rats, whereas most of these compounds increased the liver weight after consecutive administrations. The effect on the liver weight was removed by incorporation of a hydroxy group and an isopropyl group at the methylene bridge, as seen in (S)-28d and (S)-42. Selectivity for C(17,20)-lyase over 11beta-hydroxylase is also discussed, and (S)-42 was found to be a more than 260-fold selective inhibitor. Furthermore, (S)-42 showed a potent suppression of testosterone biosynthesis after a single oral administration in monkeys. These data suggest that (S)-42 may be a promising agent for the treatment of androgen-dependent prostate cancer.     

Synthesis and biological evaluation of pyridine-modified analogues of 3-(2-aminoethoxy)pyridine as novel nicotinic receptor ligands

Analogues of the potent nicotinic receptor agonist 3-(2-aminoethoxy)pyridine substituted at the 5' and 6'-positions of the pyridine ring were synthesized and tested in vitro for nicotinic receptor binding activity (displacement of [(3)H](-)cytisine from whole rat brain synaptic membranes). The substituted analogues exhibited K(i) values ranging from 0.076 to 319 nM compared to a K(i) value of 26 nM for compound 1. Among the compounds tested, 5'-vinyl-6'-chloro substituted 1 was the most potent.     

Synthesis and evaluation of 1-(benzo[b]thiophen-2-yl)ethanone analogues as novel anti-osteoporosis agents acting on BMP-2 promotor

A novel series of 1-(benzo[b]thiophen-2-yl)ethanone analogues were prepared and evaluated for enhancing BMP-2 expression. Compounds 1–5, 7, 8, 12, 13 and 16, with upregulation rate values of 35.6%, 27.9%, 39.8%, 32.0%, 37.1%, 30.2%, 28.0%, 33.5%, 22.8% and 27.3% in vitro, respectively, at a concentration of 4 μM, exhibited potent effect for enhancing BMP-2 expression. We also found that compounds 1 and 12 produced a dose-dependent increase on bone histology and histomorphometry, and effectively reduced bone defects induced by ovariectomy in an ovariectomized rat model (OVX).     

1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanones as novel CCR1 antagonists

A novel series of CCR1 antagonists based on the 1-(4-phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanone scaffold was identified by screening a compound library utilizing CCR1-expressing human THP-1 cells. SAR studies led to the discovery of the highly potent and selective CCR1 antagonist 14 (CCR1 binding IC₅₀ = 4 nM using [¹²⁵I]-CCL3 as the chemokine ligand). Compound 14 displayed promising pharmacokinetic and toxicological profiles in preclinical species.     

Synthesis and biological evaluation of 1-benzyl-5-(3-biphenyl-2-yl-propyl)-1H-imidazole as novel farnesyltransferase inhibitor

Farnesyltransferase inhibitors (FTIs) have emerged as a novel class of anti-cancer agents. Analogs of the potent FTI, 1-benzyl-5-(3-biphenyl-2-yl-propyl)-1H-imidazole, were synthesized and tested in vitro for their inhibitory activities. The most promising compound identified from this series is analog 29 that possesses potent enzymatic and cellular activities.     

Synthesis and evaluation of novel 1-(2-acylhydrazinocarbonyl)-cycloalkyl carboxamides as interleukin-1beta converting enzyme (ICE) inhibitors

Novel 1-(2-acylhydrazinocarbonyl)cycloalkyl carboxamides were designed as peptidomimetic inhibitors of interleukin-1beta converting enzyme (ICE). A short synthesis was developed and moderately potent ICE inhibitors were identified (IC(50) values <100 nM). Most of the synthesized examples were selective for ICE versus the related cysteine proteases caspase-3 and caspase-8, although several dual-acting inhibitors of ICE and caspase-8 were identified. Several of the more potent ICE inhibitors were also shown to inhibit IL-1beta production in a whole cell assay (IC(50) < 500 nM).     

Synthesis and preliminary biological evaluation of (2S,1'R,2'S)- and (2S,1'S,2'R)-2-(2'-phosphonocyclopropyl)glycines, two novel conformationally constrained l-AP4 analogues

Two novel constrained l-AP4 analogues, (2S,1'R,2'S)- and (2S,1'S,2'R)-2-(2'-phosphonocyclopropyl)glycines (7) and (8), were synthesized and evaluated as mGluR ligands. Compound 7 showed to be a group III mGluRs agonist with micromolar activity.     

1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-indoles as novel 5-HT6 receptor ligands

Novel 1-(2-aminoethyl)-3-(arylsulfonyl)-1H-indoles were prepared. Binding assays indicated they are 5-HT(6) receptor ligands, among which N,N-dimethyl-N-(2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl)amine 8t and N-methyl-N-(2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl)amine 8u showed high affinity for 5-HT(6) receptors with K(i)=3.7 and 5.7 nM, respectively.     

Identification of N-(2-(azepan-1-yl)-2-phenylethyl)-benzenesulfonamides as novel inhibitors of GlyT1

A novel series of glycine transporter 1 (GlyT1) inhibitors is described. Scoping of the heterocycle moiety of hit 4-chlorobenzenesulfonamide 1 led to replacement of the piperidine with an azepane for a modest increase in potency. Phenyl sulfonamides proved superior to alkyl and non-phenyl aromatic sulfonamides, while subsequent ortho substitution of the 2-(azepan-1-yl)-2-phenylethanamine aromatic ring yielded 39 (IC₅₀ 37 nM, solubility 14 μM), the most potent GlyT1 inhibitor in this series. Favorable brain–plasma ratios were observed for select compounds in pharmacokinetic studies to evaluate CNS penetration.     

Synthesis of furopyrazole analogs of 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole (YC-1) as novel anti-leukemia agents

As part of our continuing search for potential anticancer drug candidates in YC-1 analogs, several 1-benzyl-3-(substituted aryl)-5-methylfuro[3,2-c]pyrazoles were synthesized and evaluated for their cytotoxicity against HL-60 cell line. Among these compounds, 1-benzyl-3-(5-hydroxymethyl-2-furyl)-5-methylfuro[3,2-c]pyrazole (1) showed more potency than YC-1. Through investigation of action mechanism, it was found that compound 1 induced terminal differentiation of HL-60 cells toward granulocyte lineage and promoted HL-60 cell differentiation by regulation of Bcl-2 and c-Myc proteins. Meanwhile, compound 1 also demonstrated apoptosis inducing effect. Such anti-leukemia mechanism of action is apparently different from that of YC-1 which mainly works by inducing apoptosis, but not cell differentiation. Therefore, compound 1 is identified here as a new lead compound of cell differentiating agent and apoptosis inducer for further development of new anti-leukemia agents.     

Synthesis of N2-(substituted benzyl)-3-(4-methylphenyl)indazoles as novel anti-angiogenic agents

To search for novel compounds with potent anti-angiogenic activity, a series of N(1)-(substituted benzyl)-3-(4-methylphenyl)-1H-indazoles (16, 18, 20, 22, 24, 26, 28, 30, 32) and N(2)-(substituted benzyl)-3-(4-methylphenyl)-2H-indazoles (17, 19, 21, 23, 25, 27, 29, 31, and 33) were synthesized. The structures of these regioisomers were established by IR, UV, and NMR spectral data. 3-(4-Methylphenyl)-1H-indazole (6) and the N(2)-substituted derivatives (17, 19, 21, 23, 25, 29, 31, 33) were evaluated for their anti-angiogenic activity. Most of them showed more prominent activity than ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3). Among these tested compounds, 2-(4-chlorobenzyl)-3-(4-methylphenyl)-2H-indazole (19), 2-(4-methylbenzyl)-3-(4-methylphenyl)-2H-indazole (25), and 2-(4-methoxybenzyl)-3-(4-methylphenyl)-2H-indazole (31) showed significant anti-angiogenic activity and are worthy of further investigation.     

Synthesis and preliminary pharmacological evaluation of N-2-(4-(4-(2-substitutedthiazol-4-yl) piperazin-1-yl)-2-oxoethyl)acetamides as novel atypical antipsychotic agents

A series of N-2-(4-(4-(2-substitutedthiazol-4-yl) piperazin-1-yl)-2-oxoethyl)acetamides were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were synthesized by either microwave irradiation technique or by conventional synthesis and were characterized by spectral data (IR, (1)H NMR, and MS) and the purity was ascertained by microanalysis. All the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. D(2) antagonism studies were performed using climbing mouse assay model and 5-HT(2A) antagonism studies were performed using quipazine induced head twitches in mice. It was observed that none of the new chemical entities exhibited catalepsy. AG 3 was found to be the most active compound.     

Synthesis of six-membered prostaglandin analogues (1)

The total synthesis of two ring-homo prostaglandin analogues XIII and XV, from a common intermediate IV is described.     

Synthesis of (aryloxyacetylamino)-isonicotinic/nicotinic acid analogues as potent hypoxia-inducible factor (HIF)-1alpha inhibitors

We report a new series of HIF-1alpha inhibitors which were obtained through structural modifications of previously reported lead 1. The in vitro inhibitory potencies of newly synthesized compounds were evaluated against hypoxia-induced HIF-1 activation using cell-based reporter assay in three human cancer cell lines including SK-Hep-1, Hep3B, and AGS cells. Several compounds displayed significant inhibitory activity in all the three tested cell lines. In particular, analogue 17 displayed potent inhibition of hypoxia-induced accumulation of HIF-1alpha protein in Hep3B cell line, in addition to the dose-dependent inhibition of HIF-1 target genes VEGF and EPO.     

Synthesis and opioid activity of 2-substituted dynorphin A-(1-13) amide analogues.

A series of 2-substituted dynorphin A-(1-13) amide (Dyn A-(1-13)NH2) analogues was prepared by solid phase peptide synthesis and evaluated for opioid receptor affinities in radioligand binding assays and for opioid activity in the guinea pig ileum (GPI) assay. Amino acid substitution at the 2 position produced marked differences in both opioid receptor affinities and potency in the GPI assay; Ki values for the analogues in the radioligand binding assays and IC50 values in the GPI assay varied over three to four orders of magnitude. The parent peptide, Dyn A-(1-13)NH2, exhibited the greatest affinity and selectivity for kappa receptors and was the most potent peptide examined in the GPI assay. The most important determinant of opioid receptor selectivity and opioid potency for the synthetic analogues was the stereochemistry of the amino acid at the 2 position. Except for [D-Lys2]Dyn A-(1-13)NH2 in the kappa receptor binding assay, the analogues containing a D-amino acid at position 2 were much more potent in all of the assays than their corresponding isomers containing an L-amino acid at this position. The L-amino acid-substituted analogues generally retained some selectivity for kappa opioid receptors. The more potent derivatives with a D-amino acid in position 2, however, preferentially interacted with mu opioid receptors. Introduction of a positively charged amino acid into the 2 position generally decreased opioid receptor affinities and potency in the GPI assay.     

Synthesis of six-membered prostaglandin analogues (1)

The total synthesis of two ring-homo prostaglandin analogues XIII and XV, from a common intermediate IV is described.