Validation of a histamine H3 receptor model through structure-activity relationships for classical H3 antagonists

Histamine H(3) receptor is a G protein-coupled receptor whose activation inhibits the synthesis and release of histamine and other neurotransmitters from nerve endings and is involved in the modulation of different central nervous system functions. H(3) antagonists have been proposed for their potential usefulness in diseases characterized by impaired neurotransmission and they have demonstrated beneficial effects on learning and food intake in animal models. In the present work, a 3D model of the rat histamine H(3) receptor, built by comparative modeling from the crystallographic coordinates of bovine rhodopsin, is presented with the discussion of its ability to predict the potency of known and new H(3) antagonists. A putative binding site for classical, imidazole-derived H(3) antagonists was identified by molecular docking. Comparison with a known pharmacophore model and the binding affinity of a new rigid H(3) antagonist (compound 1, pK(i)=8.02) allowed the characterization of a binding scheme which could also account for the different affinities observed in a recently reported series of potent H(3) antagonists, characterized by a 2-aminobenzimidazole moiety. Molecular dynamics simulations were employed to assess the stability and reliability of the proposed binding mode. Two new conformationally constrained benzimidazole derivatives were prepared and their binding affinity was tested on rat brain membranes; compound 9, designed to reproduce the conformation of a known potent H(3) antagonist, showed higher potency than compound 8, as expected from the binding scheme hypothesized.     

Synthesis and structure-activity relationships of piperidine-based melanin-concentrating hormone receptor 1 antagonists

Isosteric replacement of the urea group of lead compound 1 led to novel substituted piperidine phenylamide analogues. SAR on the electron-induced effects of various linkers as well as substituents on the phenyl rings and the piperidine nitrogen has been investigated. Many single-digit nanomolar MCH R1 antagonists have been identified from this series.     

Synthesis and structure-activity relationships of 9-substituted acridines as endothelin-A receptor antagonists

Screening of a compound library against endothelin receptors (ET_A and ET_B) revealed PD 102566 (compound 1) as an ET_A selective antagonist. Synthesis and structure-activity relationships (SAR) of a series of analogs are described.     

Synthesis and structure-activity relationships of indole and benzimidazole piperazines as histamine H(4) receptor antagonists

We describe the structure-activity relationships for a series of ligands structurally related to the recently identified (5-chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (1) as histamine H(4) receptor (H(4)R) antagonists. Furthermore, we identified related benzimidazoles as novel lead compounds for the H(4)R. The ligands have been evaluated by radioligand displacement studies and functional assays for their interaction with both the human histamine H(3) and H(4) receptors and exhibit pK(i) values up to 7.5 at the human H(4)R.     

Dibasic non-imidazole histamine H3 receptor antagonists with a rigid biphenyl scaffold

A class of rigid, dibasic, non-imidazole H3 antagonists was developed, starting from a series of previously described flexible compounds. The original polymethylene chain between two tertiary amine groups was replaced by a rigid scaffold, composed by a phenyl ring or a biphenyl fragment. Modulation of the distance between the two amine groups, and of their alkyl substituents, was driven by superposition of molecular models and docking into a receptor model, resulting in the identification of 1,1'-[biphenyl-4,4'-diylbis(methylene)]bis-piperidine (5) as a subtype-selective H3 antagonist with high binding affinity (pKi=9.47) at human H3 histamine receptor.     

Synthesis and structure-activity relationships of isoxazole carboxamides as growth hormone secretagogue receptor antagonists

A series of isoxazole carboxamide derivatives has been developed as potent ghrelin receptor antagonists. The synthesis and structure-activity relationship (SAR) are described.     

Structure-activity relationships of arylbenzofuran H3 receptor antagonists

An SAR study of histamine H3 receptor antagonists based on substituted (R)-2-methyl-1-[2-(5-phenyl-benzofuran-2-yl)-ethyl]-pyrrolidines is presented.     

Synthesis and structure-activity relationships of piperidinylpyrrolopyridine derivatives as potent and selective H1 antagonists

The synthesis and structure-activity relationships of piperidinylpyrrolopyridines as potent and selective H(1) antagonists are discussed. It was found that the nature of the acid chain bonded to piperidine was a key feature for maintaining both the duration of action in vivo and lack of sedative properties.     

Synthesis, structure-activity relationships, and anxiolytic activity of 7-aryl-6,7-dihydroimidazoimidazole corticotropin-releasing factor 1 receptor antagonists

7-Aryl-6,7-dihydroimidazoimidazoles represent a novel series of high-affinity corticotropin-releasing factor 1 receptor antagonists. Here, we report their synthesis and SAR as well as behavioral activity of two exemplary compounds, 7b and 7k, in a mouse canopy model of anxiety.     

Synthesis and structure-activity relationships of TEI-9647 derivatives as Vitamin D3 antagonists

The Vitamin D(3) lactone analogues, (23S)- and (23R)-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647 and TEI-9648) are antagonists of the 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) nuclear receptor (VDR)-mediated differentiation of human leukemia (HL-60) cells. In order to clarify the structure-Vitamin D antagonistic activity relationship, we paid attention to the unique lactone moiety of TEI-9647 and TEI-9648: alpha-exo-methylene-gamma-lactone structure. We synthesized the exo-methylene-modified analogues (methylene saturated, endo-methylene, methylene-deleted, methyl-substituted, dimethyl-substituted, methylene-replaced with dimethyl and cyclopropane) and oxygen-modified analogues (oxygen atom replaced with nitrogen and carbon atom) by convergent method using palladium-catalyzed coupling reaction or direct modification of VD(3) skeleton. The antagonistic activity in HL-60 cell differentiation evaluating system of these analogues revealed that any exo-methylene-modified analogues and nitrogen analogue did not have the antagonistic activity, on the other hand carbon analogue did show. The results suggest that "alpha-exo-methylene carbonyl" structure of VD(3) side-chain is crucial for antagonistic activity. The structure is integral building block of many natural products which have interesting biological and it is thought that Michael-type addition of alpha-exo-methylene carbonyl structure with protein nucleophiles such as cysteine would play an important role for the activities. According to this theory, Michael-type reaction of TEI-9647 and TEI-9648 with cysteine residue in protein related to VDR/VDRE-mediated genomic actions such as VDR would be essential step of the antagonistic action.     

Nonpeptide Urotensin-II receptor agonists and antagonists: review and structure-activity relationships

Human Urotensin-II (hU-II) is a cyclic 11-amino acid peptide that plays a role in cardiovascular homeostasis. Its receptor is a member of the class A of G-protein-coupled receptors, called GPR14. In recent years, several nonpeptide ligands have been reported in the literature. Most were identified by high-throughput screening and optimized by medicinal chemistry methods. Other nonpeptide ligands were discovered starting from the 3D structure of hU-II or other ligands. They were identified by a virtual screening approach based on a 3D pharmacophore or by structural similarity with others cyclic peptides. In this review, nonpeptide agonists and antagonists are presented in relation to structure-activity relationships.     

Synthesis and structure-activity relationships of new disubstituted phenyl-containing 3,4-diamino-3-cyclobutene-1,2-diones as CXCR2 receptor antagonists

A series of 3,4- and 3,5-disubstituted phenyl-containing cyclobutenedione analogues were synthesized and evaluated as CXCR2 receptor antagonists. Variations in the disubstitution pattern of the phenyl ring afforded new compounds with potent CXCR2 binding affinity in the low nanomolar ranges. Moreover, two potent compounds 19 and 26 exhibited good oral pharmacokinetic profiles.     

Synthesis and structure-activity relationships of 3,4-diaminocyclobut-3-ene-1,2-dione CXCR2 antagonists

A novel series of 3,4-diaminocyclobut-3-ene-1,2-diones was prepared and found to show potent inhibitory activity of CXCR2 binding and IL-8-mediated chemotaxis of a CXCR2-expressing cell line. Microsome stability and Caco2 studies were subsequently used to show that compounds of this chemotype are predicted to have good oral bioavailability and are thus suitable for pharmaceutical development.     

Synthesis and structure-activity relationships for new 6-fluoroquinoline derivatives with antiplasmodial activity

The substitution of 6-fluoroquinolines was modified in ring positions 2 and 4. The new compounds were tested in vitro for their activities against a sensitive and a multidrug resistant strain of Plasmodium falciparum. Some physicochemical parametres were calculated (log P, log D, ligand efficiency) or determined experimentally (permeability). The most promising compounds were tested for their in vivo activity against Plasmodium berghei in a mouse model. The 6-fluoro-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-N-[2-(pyrrolidin-1-yl)ethyl]quinoline-4-carboxamide possessed proper physicochemical properties and showed high antiplasmodial activity in vitro (IC₅₀?≤?0.0029?µM) and in vivo (99.6% activity).     

Identification and structure-activity relationships of 1-aryl-3-piperidin-4-yl-urea derivatives as CXCR3 receptor antagonists

The synthesis and biological evaluation of a series of 1-aryl-3-piperidin-4-yl-urea derivatives as small-molecule CXCR3 antagonists is described. SAR studies resulted in significant improvement of potency and physicochemical properties and established the key pharmacophore of the series, and led to the identification of 9t, which exhibits an IC50 of 16 nM in the GTPgammaS35 functional assay.     

Synthesis and structure-activity relationships of heteroaryl substituted-3,4-diamino-3-cyclobut-3-ene-1,2-dione CXCR2/CXCR1 receptor antagonists

Comprehensive SAR studies were undertaken in the 3,4-diaminocyclobut-3-ene-1,2-dione class of CXCR2/CXCR1 receptor antagonists to explore the role of the heterocycle on chemokine receptor binding affinities, functional activity, as well as oral exposure in rat. The nature of the heterocycle as well as the requisite substitution pattern around the heterocycle was shown to have a dramatic effect on the overall biological profile of this class of compounds. The furyl class, particularly the 4-halo adducts, was found to possess superior binding affinities for both the CXCR2 and CXCR1 receptors, functional activity, as well as oral exposure in rat versus other heterocyclic derivatives.     

Discovery and structure-activity relationships of 2-benzylpyrrolidine-substituted aryloxypropanols as calcium-sensing receptor antagonists

A structure-activity relationship study of the amine portion of the calcilytic compound NPS-2143 resulted in the discovery of substituted 2-benzylpyrrolidines as replacements for the 1,1-dimethyl-2-naphthalen-2-yl-ethylamine. When compared to NPS-2143, a newly discovered compound, 3h, exhibited similar potency as a calcium-sensing receptor (CaR) antagonist and a superior human ether-a-go-go related gene (hERG) profile.     

Synthesis and SAR of novel histamine H3 receptor antagonists

The synthesis and biological evaluation of novel tetrahydroisoquinoline, tetrahydroquinoline, and tetrahydroazepine antagonists of the human and rat H(3) receptors are described. The substitution around these rings as well as the nature of the substituent on nitrogen is explored. Several compounds with high affinity and selectivity for the human and rat H(3) receptors are reported.     

Synthesis and structure-activity relationships of thieno[2,3-b]pyrroles as antagonists of the GnRH receptor

A new class of small-molecule GnRH antagonists, the thieno[2,3-b]pyrroles, was designed. Herein, the synthesis and structure-activity relationships are described. Substitution at the C4 position was investigated; during this study, it was observed that introducing piperazines and piperidines improved the physical properties of the compounds while retaining good in vitro potency. This exploration led to the discovery of amidopiperidines with improved pharmacokinetic properties.     

Identification and structure-activity relationships of a new series of Melanocortin-4 receptor antagonists

The identification and optimization of a series of acylguanidine-based melanocortin-4 receptor antagonists is discussed.