Fluorescent non-imidazole histamine H3 receptor ligands with nanomolar affinities

Omega-piperidinoalkanamine derivatives with fluorescent moieties (2-cyanoisoindol-1-yl, 7-nitrobenzofurazan-4-yl) have been synthesized starting from piperidine in three steps. The compounds display moderate to good histamine hH(3) receptor affinities with K(i) values ranging from 178 to 11nM. The new compounds may act as tools for identification and understanding of the binding site on the histamine H(3) receptor.     

Ether derivatives of 3-piperidinopropan-1-ol as non-imidazole histamine H3 receptor antagonists

A series of aliphatic and aromatic ether derivatives of 3-piperidinopropan-1-ol has been prepared by four different methods. The ethers obtained were evaluated for their affinities at recombinant human histamine H3 receptor, stably expressed in CHO-K1 or HEK 293 cells. All compounds investigated show from moderate to high in vitro affinities in the nanomolar concentration range. Selected compounds were investigated under in vivo conditions after oral administration to mice. Some proved to be highly potent and orally available histamine H3 receptor antagonists. The most potent antagonists in this series have been in vitro the 4-(1,1-dimethylpropyl)phenyl ether 19 (hH3R K(i) = 8.4 nM) and in vivo the simple ethyl ether 2 (ED50 = 1.0mg/kg).     

Fluorinated non-imidazole histamine H3 receptor antagonists

Fluorine substituents have become a widespread and important component in drug design and development. Here, the synthesis of fluorine containing compounds and some corresponding precursor molecules are presented for potential isotope labelling as well as their data obtained with in vitro and in vivo screenings. The compounds vary in the basic centres (piperidine or pyrrolidine) and are fluoro substituted in different positions of the basic alicyclic moiety. Pharmacological evaluation resulted in ligands with high affinities at hH₃ receptor in the nanomolar and subnanomolar concentration range and some with high antagonist in vivo potencies.     

Piperidine variations in search for non-imidazole histamine H(3) receptor ligands

Synthesis and biological evaluation of the novel histamine H(3) receptor ligands is described. Two series of ethers (aliphatic and aromatic) have been prepared by four different methods. Compounds were evaluated for their affinities at recombinant human H(3) receptor stably expressed in CHO cells. The ethers show from low to moderate in vitro affinities in nanomolar concentration range. The most potent compound was the 1-[3-(4-tert-butylphenoxy)propyl]-4-piperidino-piperidine 16 (hH(3)R K(i)=100 nM). Several members of the new series investigated under in vivo conditions, proved to be inactive.     

Alkyl derivatives of 1,3,5-triazine as histamine H4 receptor ligands

This study focuses on the design, synthesis, molecular modeling and biological evaluation of a novel group of alkyl-1,3,5-triazinyl-methylpiperazines. New compounds were synthesized and their affinities for human histamine H₄ receptor (hH₄R) were evaluated. Among them, 4-(cyclohexylmethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (14) exhibited hH₄R affinity with a K_i of 160?nM and behaved as antagonist in functional assays: the cellular aequorin-based assay (IC₅₀?=?32?nM) and [³⁵S]GTPγS binding assay (pK_b?=?6.67). In addition, antinociceptive activity of 14 in vivo was observed in Formalin test (in mice) and in Carrageenan-induced acute inflammation test (in rats).     

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.     

Discovery of substituted benzyl tetrazoles as histamine H3 receptor antagonists

A series of potent and subtype selective H3 receptor antagonists containing a novel tetrazole core and diamine motif is reported. A one-pot multi-component Ugi reaction was utilised to rapidly develop the structure–activity relationships (SAR) of these compounds. Optimisation for liver microsome stability (t_1/2 >60 min), minimal CYP inhibition (IC₅₀ >50 μM) and high cell permeability (Caco-2 P_app >20 × 10^?6 cm/s) identified several compounds with drug-like properties.     

The synthesis of substituted fluorenes as novel non-imidazole histamine h(3) inhibitors

A novel non-imidazole fluorene oxime 1a has been identified as a histamine H(3) inhibitor, and its structure-activity relationship has been evaluated.     

Benzimidazole-substituted (3-phenoxypropyl)amines as histamine H3 receptor ligands

A series of non-imidazole histamine H(3) receptor antagonists based on the (3-phenoxypropyl)amine motif, which is a common pharmacophore for H(3) antagonists, has been identified. A preliminary SAR study around the amine moiety has identified 8a as a potent H(3) antagonist possessing a good pharmacokinetic profile in the rat.     

Piperidino-hydrocarbon compounds as novel non-imidazole histamine H(3)-receptor antagonists

In search for novel non-imidazole histamine H(3)-receptor antagonists, piperidino-hydrocarbon compounds were synthesized using the known non-imidazole histamine H(3)-receptor antagonist FUB 637 (3-phenylpropyl 3-piperidinopropyl ether) as lead structure. Piperidino-alkyl derivatives containing highly flexible side chains (2, 4-7) were prepared via N-alkylation. Compounds containing unsaturated alkyl groups were synthesized in order to investigate the impact of rigidifying the side chain (8-16). Terminal alkynes were prepared by alkylation of lithium acetylide-ethylenediamine complex, disubstituted alkynes were synthesized by alkylation of the appropriate acetylene in the presence of n-butyllithium-N,N,N',N'-tetramethylene-ethylene-diamine complex. The novel compounds were investigated in an in vitro functional assay on the guinea-pig ileum, in which N-(7-phenylhept-3-ynyl)piperidine (14) proved to be of good potency in this class (pA(2)=7.21). In an in vivo assay the compounds were additionally screened for their abilities to influence central H(3)-histaminergic neuron activity in mice with regard to their oral availabilities and distribution properties. In this screening, N-pent-4-ynylpiperidine (9) and N-hex-5-ynylpiperidine (10) proved to be highly potent and orally available histamine H(3)-receptor antagonists. The ED(50) values for 9 and 10 were 1.3 and 1.4mg/kg po, respectively, which is in the potency range of the reference antagonist thioperamide.     

Structure-activity relationships of non-imidazole H(3) receptor ligands. Part 1

SAR studies for novel non-imidazole containing H(3) receptor antagonists with high potency and selectivity for rat H(3) receptors are described. A high throughput screening lead, A-923, was further elaborated in a systematic manner to clarify a pharmacophore for this class of aryloxyalkyl piperazine based compounds.     

Chlorophenoxy aminoalkyl derivatives as histamine H3R ligands and antiseizure agents

A series of twenty new chlorophenoxyalkylamine derivatives (9–28) was synthesized and evaluated on their binding properties at the human histamine H₃ receptor (hH₃R). The spacer alkyl chain contained five to seven carbon atoms. The highest affinities have shown the 4-chloro substituted derivatives 10 and 25 (K_i = 133 and 128 nM, respectively) classified as antagonists in cAMP accumulation assay (EC₅₀ = 72 and 75 nM, respectively). Synthesized compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Two compounds (4-chloro substituted derivatives: 20 and 26) were the most promising and showed in the MES seizure model in rats (after ip administration) ED₅₀ values of 14 mg/kg and 13.18 mg/kg, respectively. Protective indexes (PI = TD₅₀/ED₅₀) were 3.2 for 20 and 3.8 for 26. Moreover, molecular modeling and docking studies were undertaken to explain affinity at hH₃R of target compounds, and the experimentally and in silico estimation of properties like lipophilicity and metabolism was performed. Antiproliferative effects have been also investigated in vitro for selected compounds (10 and 25). These compounds neither possessed significant antiproliferative and antitumor activity, nor modulated CYP3A4 activity up to concentration of 10 μM.     

N-Alkenyl and cycloalkyl carbamates as dual acting histamine H3 and H4 receptor ligands

Previous studies have shown that several imidazole derivatives possess affinity to histamine H(3) and H(4) receptors. Continuing our study on structural requirements responsible for affinity and selectivity for H(3)/H(4) receptor subtypes, two series of 3-(1H-imidazol-4-yl)propyl carbamates were prepared: a series of unsaturated alkyl derivatives (1-9) and a series possessing a cycloalkyl group different distances to the carbamate moiety (10-13). The compounds were tested for their affinities at the human histamine H(3) receptor, stably expressed in CHO-K1 cells. Compounds 1, 2, 5-7, 10-13 were investigated for their affinities at the human histamine H(4) receptor co-expressed with Gα(i2) and Gβ(1)γ(2) subunits in Sf9 cells. To expand the pharmacological profile, compounds were further tested for their H(3) receptor antagonist activity on guinea pig ileum and in vivo after oral administration to mice. All tested compounds exhibited good affinity for the human histamine H(3) receptor with K(i) values in the range from 14 to 194nM. All compounds were active in vivo after peroral administration (p.o.) to Swiss mice, thus demonstrating their ability to cross the blood-brain barrier. The most potent H(3) receptor ligand of these series was compound 5, 3-(1H-imidazol-4-yl)propyl pent-4-enylcarbamate with the highest affinity (K(i)=14nM). Additionally, compound 3 showed remarkable central nervous system (CNS) H(3)R activity, increasing the N(τ)-methylhistamine levels in mice with an ED(50) value of 0.55mg/kg, p.o. evidencing therefore, a twofold increase of inverse agonist/antagonist potency compared to the reference inverse agonist/antagonist thioperamide. In this study, the imidazole propyloxy carbamate moiety was kept constant. The different lipophilic moieties connected to the carbamate functionality in the eastern part of the molecule had a range of influences on the human H(4) receptor affinity (154-1326nM).     

Rasagiline derivatives combined with histamine H3 receptor properties

The irreversible monoamine oxidase B (MAO B) inhibitor rasagiline has been described with multiple disease modifying effects in vitro on models of Parkinson’s disease. The combination of this established drug to recently developed histamine H₃ receptor (H₃R) antagonist elements gives new impetus to the design of multitargeting ligands. Surprisingly, the 5-substituted 3-piperidinopropyloxy rasagiline derivative 1 was more potent on both targets than its 6-substituted isomer. It showed nanomolar affinities at the desired targets (MAO B IC₅₀ = 256 nM; hH₃R K_i = 2.6 nM) with a high preference over monoamine oxidase A (MAO A) and negligible affinity at histamine H₁, H₄, dopamine D₂, D₃ receptors or acetyl-/butyrylcholinesterases.     

Structure-activity relationships of non-imidazole H(3) receptor ligands. Part 3: 5-Substituted 3-phenyl-1,2,4-oxadiazoles as potent antagonists

Further SAR studies on novel histamine H(3) receptor antagonists are presented. Compound 14bb is a potent antagonist of both the rat cortical and human clone receptors, and is demonstrated to act functionally as an antagonist in an in vivo mouse dipsogenia model.     

Novel substituted pyrrolidines are high affinity histamine H3 receptor antagonists

Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H₃ receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H₃ receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate.     

Structural modifications and in vitro pharmacological evaluation of 4-pyridyl-piperazine derivatives as an active and selective histamine H3 receptor ligands

A novel series of 4-pyridylpiperazine derivatives with varying alkyl linker length and eastern part substituents proved to be potent histamine H₃ receptor (hH₃R) ligands in the nanomolar concentration range. While paying attention to their alkyl linker length, derivatives with a six methylene linker tend to be more potent than their five methylene homologues. Moreover, in the case of both phenoxyacetyl- and phenoxypropionyl- derivatives, an eight methylene linkers possess lower activity than their seven methylene homologues. However, in global analysis of collected data on the influence of alkyl linker length, a three methylene homologues appeared to be of highest hH₃R affinity among all described 4-pyridylpiperazine derivatives from our group up to date. In the case of biphenyl and benzophenone derivatives, compounds with para- substituted second aromatic ring were of higher affinity than their meta analogues. Interestingly, benzophenone derivative 18 showed the highest affinity among all tested compounds (hH₃R K_i = 3.12 nM). The likely protein-ligand interactions, responsible for their high affinity were demonstrated using molecular modeling techniques. Furthermore, selectivity, intrinsic activity at H₃R, as well as drug-like properties of selected ligands were evaluated using in vitro methods.     

Benzylpiperidine variations on histamine H3 receptor ligands for improved drug-likeness

Several hH₃R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. Nevertheless, many promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity and their dibasic character. Analysis of previously, as potential PET ligands synthesized compounds (ST-889, ST-928) revealed promising results concerning physicochemical properties and drug-likeness. Herein, the synthesis, the evaluation of the binding properties at the hH₃R and the estimation of different physicochemical and drug-likeness properties of further novel benzylpiperidine variations on H₃R antagonists is described. Due to the introduction of various small hydrophilic moieties in the structure, drug-likeness parameters have been improved. For instance, compound 12 (ST-1032) showed in addition to high affinity at the H₃R (pK_i (hH₃R) = 9.3) c log S, c log P, LE, LipE, and LELP values of −2.48, 2.18, 0.44, 7.14, and 4.95, respectively. Also, the keto derivative 5 (ST-1703, pK_i (hH₃R) = 8.6) revealed LipE and LELP values of 5.25 and 6.84, respectively.     

Identification of 2-arylbenzimidazoles as potent human histamine H4 receptor ligands

A series of 2-arylbenzimidazoles was synthesized and found to bind with high affinity to the human histamine H(4) receptor. Structure-activity relationships were investigated through library preparation and evaluation as well as traditional medicinal chemistry approaches, leading to the discovery of compounds with single-digit nanomolar affinity for the H(4) receptor.     

Biaryl piperidines as potent and selective delta opioid receptor ligands

The design and synthesis of novel opiates are reported. Based on the message-address principle a novel class of 4,4- and 3,3-biaryl piperidines was designed and synthesized. Biological evaluation confirmed that these compounds exhibit high affinity and selectivity for the delta opioid receptor. Key structure–activity relationships that influence affinity, selectivity, functional activity and clearance are reported.