2-(Anilinomethyl)imidazolines as alpha1 adrenergic receptor agonists: alpha1a subtype selective 2'-heteroaryl compounds

The structure-activity relationship of 2'-pyrrole, pyrazole and triazole substituted 2-(anilinomethyl)imidazolines as alpha(1) adrenergic agonists was investigated. The size and orientation of substituents, as well as the position of the heteroatoms, were found to have a profound effect on the potency and selectivity of the molecules. Potent alpha(1A) subtype selective agonists have been identified.     

alpha(1)-Adrenoceptor agonists: the identification of novel alpha(1A )subtype selective 2'-heteroaryl-2-(phenoxymethyl)imidazolines

Novel 2'-heteroaryl-2-(phenoxymethyl)imidazolines have been identified as potent agonists of the cloned human alpha(1)-adrenoceptors in vitro. The nature of the 2'-heteroaryl group can have significant effects on the potency, efficacy, and subtype selectivity in this series. alpha(1A) Subtype selective agonists have been identified.     

2-(anilinomethyl)imidazolines as alpha1A adrenergic receptor agonists: 2'-heteroaryl and 2'-oxime ether series

A series of 2'-heteroaryl and 2'-oxime anilinomethylimidazolines was prepared and evaluated in in vitro functional assays for cloned human alpha1A, alpha1B, and alpha1D receptor subtypes. Potent and selective alpha1A agonists have been identified in these series.     

Pharmacophore identification of alpha(1A)-adrenoceptor antagonists

A chemical feature based pharmacophore model was developed for alpha(1A)-adrenoceptor antagonists by HypoGen module implemented in catalyst software package. The best scoring pharmacophore hypothesis, Hypo1, consisted of four important chemical features (one positive ion, one hydrogen-bond donor, one aromatic ring, and one hydrophobic group). The results of our study provide a valuable tool in designing new leads with desired biological activity by virtual screening.     

A lipophilic, selective alpha1 -adrenoceptor agonist: 2-(2-chloro-5-trifluoromethylphenylimino)imida-zolidine (St 587)

A new compound (St 587) is described, which is a selective α₁ -adrenoceptor stimulating agent with lipophilic properties. This combination of characteristics is novel, since all α₁ -adrenoceptor agonists developed so far are hydrophilic. The α-adrenergic effects of 2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587), a derivative of clonidine, were examined in several animal models. St 587 (1–10,000 μg/kg, i.v.) induced vasoconstriction in pithed, normotensive rats. This peripheral pressor activity was strongly antagonized by prazosin (0.1 mg/kg), but not affected by yohimbine (1 mg/kg). In intact, pentobarbitone-anaesthetized normotensive rats, St 587 (1–3,000 μg/kg, i.v.) evoked transient pressor responses, but a secondary fall in blood pressure and cardiac frequency was not observed. In pitched rats, St 587 (1–1,000 μg/kg) failed to modify the increase in heart rate produced by electrical stimulation of the cardioaccelerator sympathetic nerve fibres. St 587 (300 and 1,000 μg/kg) did not display central hypotensive activity, when injected into the left vertebral artery of anaesthetized cats. In addition, no hypotensive effect was observed when St 587 was administered i.v. to anaesthetized normotensive rats and cats. In mice, St 587 (10–10,000 μg/kg, i.p.) lacked sedative properties, since it did not prolong the hexobarbitone (75 mg/kg, i.p.)-induced loss of the righting reflex. The overall lipophilicity (log P′) of St 587 in the octanol/buffer (pH=7.4) reference system at 37°C amounted to 1.54. The experimental data suggest that St 587 is a lipophillic compound with selective α₁ - agonistic activity. The inability of St 587 to cause hypotension and sedation provides further evidence for the view that α₁ -adrenoceptors in the brain are not involved in the central hypotensive action and the sedation, caused by clonidine and related drugs. These effects are solely mediated by homogenous populations of α₂ -adrenoceptors.     

3-Acyloxy-2-phenalkylpropyl amides and esters of homovanillic acid as novel vanilloid receptor agonists

A series of 3-acyloxy-2-phenalkylpropyl amides and esters of homovanillic acid were designed and synthesized as vanilloid receptor agonists containing the three principal pharmacophores of resiniferatoxin. Amide analogues 23, 5 and 11 were found to be potent agonists in vanilloid receptor assay both for ligand binding and for activation.     

Novel 2-imidazoles as potent and selective alpha1A adrenoceptor partial agonists

Novel 2-imidazoles have been identified as potent partial agonists of the α_1A adrenergic receptor, with good selectivity over the α_1B, α_1D and α_2A receptor sub-types. Sulfonamide 23 possessed attractive drug-like properties with respect to physicochemical and ADME properties and wide ligand selectivity.     

Distribution of alpha1-adrenoceptor subtype mRNA and identification of subtype responsible for renovascular contraction in human renal artery

This study was intended to quantify the amounts of the alpha1-adrenoceptor subtype mRNAs in human renal artery and to demonstrate the distribution of receptor subtypes responsible for the contraction of the renal artery. RNase protection assay showed that the mean amount of alpha1a mRNA was much greater than that of alpha1b or alpha1d mRNAs in both the main and branch renal arteries. However, the abundance of alpha1a mRNA in human renal artery was much less than in our previous data in the prostate. In situ hybridization showed that all alpha1 subtype mRNAs were localized in the smooth muscle cells of the tunica media of the artery, and the distribution pattern of these three mRNAs in the main artery was the same as in the branch artery. However, the intensity of signals for alpha1d and alpha1b antisense RNAs probes was lower than that for the alpha1a antisense RNA probe. In the functional study, concentration-response curves to noradrenaline pretreated with KMD-3213, an alpha1A/L-adrenoceptor selective antagonist, seemed to be biphasic in nature. Chloroethyclonidine (CEC) failed to inactivate the noradrenaline-induced contraction, and prazosin showed relatively low affinity with a pA2 value of 8.8. These data suggest that the alpha1A/L-adrenoceptor mediates primarily those responses to noradrenaline in this artery. The other alpha1-adrenoceptor subtypes could also mediate the secondary contractile response to noradrenaline in this artery.     

Imidazo[1,2-b][1,2,4]triazines as alpha2/alpha3 subtype selective GABA A agonists for the treatment of anxiety

Imidazo[1,2-a]pyrimidines and imidazo[1,2-b][1,2,4]triazines are ligands for the benzodiazepine binding site of GABA(A) receptors that are functionally selective for the alpha2/alpha3 subtypes over the alpha1 subtype. SAR studies to optimise this functional selectivity, pharmacokinetic and behavioural data are described.     

Nipecotic and iso-nipecotic amides as potent and selective somatostatin subtype-2 receptor agonists

N-Substituted nipecotic and iso-nipecotic amides of beta-methylTrpLys tert-butyl ester were found to be novel, selective and potent agonists of the somatostatin subtype-2 receptor in vitro. For example iso-nipecotic amide 8a showed high hsst2 binding affinity (Ki = 0.5 nM) and good selectivity (h5/h2 = 832).     

Antimicrobial effects of esters and amides of 3-(5-nitro-2-furyl)acrylic acid

The effect of 18 newly synthesized esters and amides of 3-(5-nitro-2-furyl)acrylic acid on bacteria (Escherichia coli, Staphylococcus aureus), yeasts (Saccharomyces cerevisiae, Candida albicans), molds (Aspergillus niger, Penicillium cyclopium, Rhizopus oryzae) and algae (Chlorella pyrenoidosa, Euglena gracilis, Scenedesmus obliquus) was investigated. The MIC values revealed antimycotic, antialgal and antibacterial activity of the studied derivates. The antimycotic activity was found to decrease with increasing the length of the alkyl chain of esters and after introduction of amino nitrogen into the furylethylene backbone. The inhibitory effect on growth is caused by blocking bioenergetic processes, glycolysis in particular.     

Novel 2-imidazoles as potent, selective and CNS penetrant alpha1A adrenoceptor partial agonists

A novel series of central nervous system (CNS) penetrant indane 2-imidazoles have been identified as potent, partial agonists of the alpha(1A) adrenergic receptor, having good selectivity over the alpha(1B), alpha(1D) and alpha(2) sub-types. A key structural motif to impart selectivity is a methylene spacer between the indane and a pendant substituent, which includes heterocycles, sulphones and ethers. Introduction of an ortho-halogen to this group led to a lowering of intrinsic efficacy (E(max)).     

N-[[1-(2-phenylethyl)pyrrolidin-2-yl]methyl]cyclohexanecarboxamides as selective 5-HT1A receptor agonists

A series of benzamides was synthesized as selective agonists for the 5-HT1A receptor. It was found that (S)-N-[[1-(2-phenylethyl)pyrrolidin-2-yl]methyl]cyclohexanecarb oxamide(7-(S)) has potent and selective agonistic activity for the 5-HT1A receptor (5-HT1A; Ki 0.49 nmol/L, D2; IC50 = >1000 nmol/L, 5-HT2; Ki = 240 nmol/L).     

2-(Anilino)imidazolines and 2-(benzyl)imidazoline derivatives as h5-HT1D serotonin receptor ligands

2-(Anilino)imidazolines were identified as novel human 5-HT(1D) receptor ligands, but offered no particular advantage over previously reported 2-(benzyl)imidazolines. Pharmacokinetic and functional data were obtained for selected 2-(benzyl)imidazoline derivatives.     

Synthesis of amides from (E)-3-(1-chloro-3,4-dihydronaphthalen-2-yl)acrylic acid and substituted amino acid esters as NorA efflux pump inhibitors of Staphylococcus aureus

Inhibitors for NorA efflux pump of Staphylococcus aureus have attracted the attention of many researchers towards the discovery and development of novel efflux pump inhibitors (EPIs). In an attempt to find specific potent inhibitors of NorA efflux pump of S. aureus, a total of 15 amino acid conjugates of 3-(1-chloro-3,4-dihydronaphthalen-2-yl)acrylic acid (4–18) were synthesized using a simple convenient synthetic approach and bioevaluated against NorA efflux pump. Two compounds 7 and 8 (each having MEC of 1.56?µg/mL) were found to restore the activity of ciprofloxacin through reduction of the MIC elucidated by comparing the ethidium bromide efflux in dose dependent manner in addition to ethidium bromide efflux inhibition and accumulation study using NorA overexpressing strain SA-1199B. Most potent compounds among these were able to restore the antibacterial activity of ciprofloxacin completely against SA-1199B. Structure activity relationship (SAR) studies and docking study of potent compounds 7 and 8 could elucidate the structural requirements necessary for interaction with the NorA efflux pumps. On the whole, compounds 7 and 8 have ability to reverse the NorA efflux mediated resistance and could be further optimized for development of potent efflux pump inhibitors.     

(2R)-2-methylchromane-2-carboxylic acids: discovery of selective PPARalpha agonists as hypolipidemic agents

A SAR study was conducted on chromane-2-carboxylic acid toward selective PPARalpha agonisim. As a result, highly potent, and selective PPARalpha agonists were discovered. The optimized compound 43 exhibited robust lowering of total cholesterol levels in hamster and dog animal models.     

Lactams as EP4 prostanoid receptor subtype selective agonists. Part 1: 2-Pyrrolidinones-stereochemical and lower side-chain optimization

A series of 7-[(5R)-substituted 2-oxo-1-pyrrolidinyl]-heptanoic acids were prepared, their isomeric purity determined, and pharmacologically evaluated. Lactams with affinity for the EP(4) receptor displayed agonist behavior. The lower side-chain of the lactam template could be substituted to afford ligands (e.g., 17, 24, 30, 31, and 33) of high potency and greater than 1000-fold affinity for EP(4) versus the other EP prostanoid receptors.     

Beta(3)-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl)phenoxy]-2-methylpropionic acid.

In a search for novel analogues of β₃-adrenoceptor (AR) agonists relaxing the bladder for treatment of urinary dysfunction, 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)phenoxy]-2-methylpropionic acids (1a–e), into which a fibrate-like structure had been incorporated, were synthesised. Compound 1a was found to be a selective β₃-AR agonist in functional assays using the ferret detrusor (β₃-AR), rat uterus (β₂-AR), and rat atrium (β₁-AR); β₃: EC₅₀=7.8 nM, β₂: IC₅₀=7,300 nM, β₁: EC₂₀=23,000 nM. The introduction of a chlorine atom or methyl substituent at the ortho-position on the phenyl ring of 1a further improved β₃-AR selectivity. In an in vivo study, 1a lowered intrabladder pressure (ED₅₀=31 μg/kg) in rats, without increasing heart rate, in keeping with the in vitro results. Consequently, it is proposed that 1a and its analogues (1b–e), possess β₃-AR agonistic activity in the absence of undesirable β₁- or β₂-AR mediated actions, and may be useful for clinical treatment and pharmacological studies.     

Discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB2 agonists

Recently sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Replacing the sulfonamide functionality and reversing the original carboxamide bond led to the discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB₂ agonists. Selective CB₂ agonist 31 (K_i = 2.7; CB₁/CB₂ = 190) displayed robust activity in a rodent model of postoperative pain.     

MMP-13 selective alpha-sulfone hydroxamates: identification of selective P1' amides

Continuing our interest in designing compounds preferentially potent and selective for MMP-13, we report on a series of hydroxamic acids with a flexible amide P1′ substituents. We identify an amide which spares both MMP-1 and -14, and shows >500 fold selectivity for MMP-13 versus MMP-2 and -8.