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.     

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.     

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.     

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.     

Diether derivatives of homo- or substituted piperidines as non-imidazole histamine H3 receptor ligands

Synthesis and biological activities of a series of homo- or substituted piperidine unsymmetrical diethers are described. The novel compounds were evaluated for histamine H₃ receptor binding affinities at recombinant human H₃ receptor stably expressed in HEK-293 cells. All diethers showed in vitro affinities in nanomolar concentration range. The most potent compounds are 1-[3-(3-(4-chlorophenoxy)propoxy)propyl]-3-methylpiperidine 11 (K_i = 3.2 nM) and 1-[3-(3-(4-chlorophenoxy)propoxy)propyl]azepane 13 (K_i = 3.5 nM).     

Structure-activity relationships of adenosine A3 receptor ligands: new potential therapy for the treatment of glaucoma

Structure-activity relationships (SAR) of fused 1,2,4-triazolo[1,5-c ]pyrimidine were performed. Various substituents were introduced into the heterocyclic ring to improve the potency of adenosine A(3) receptor binding affinity and A(3)-selectivity against other subtypes. Potent and selective A(3) receptor antagonists were identified and were evaluated in a monkey model of intraocular pressure by eye-drop administration. As a result, compound 1c (OT-7999) was found to significantly decrease intraocular pressure in the animal model.     

A new class of potent non-imidazole H(3) antagonists: 2-aminoethylbenzofurans

2-aminoethylbenzofurans constitute a new class of H(3) antagonists that are more rotationally constrained than most previously reported H(3) antagonists. They retain high potency at human and rat receptors, with efficient CNS penetration observed in 35. The SAR of the basic amine moiety was compared in three different series of analogues. The greatest potency was found in analogues bearing a 2-methylpyrrolidine, a 2,5-dimethylpyrrolidine, or a 2,6-dimethylpiperidine.     

Structure-activity relationships of 3-substituted N-benzhydryl-nortropane analogs as nociceptin receptor ligands for the treatment of cough

A series of 3-axial-aminomethyl-N-benzhydryl-nortropane analogs have been synthesized and identified to bind to the nociceptin receptor with high affinity. Many of these analogs showed high binding selectivity over classic opioid receptors such as mu receptor. The synthesis and structure-activity relationships around the C-3 nortropane substitution are described. Selected compounds with potent oral antitussive activity in the guinea pig model are disclosed.     

Novel and highly potent histamine H3 receptor ligands. Part 2: exploring the cyclohexylamine-based series

Synthesis and biological evaluation of novel and potent cyclohexylamine-based histamine H3 receptor inverse agonists are described. Compounds in this newly identified series exhibited subnanomolar binding affinities for human receptor and no significant interaction with hERG channel. One derivative (10t) demonstrated enhanced in vivo efficiency and preferential brain distribution, both properties suitable for potential clinical evaluation.     

Structure-activity relationships of 2-Aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)-ones at the benzodiazepine receptor

A large series of 2-aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)ones (PIs) carrying properly selected substituents at the indole and N₂-phenyl rings was prepared and tested as central benzodiazepine receptor (BZR) ligands and potential (anti)convulsant agents. Stereoelectronic requirements for high receptor affinity were detected by means of 2-D and 3-D QSAR analyses. BZR affinities and pharmacological profiles of the compounds were examined in comparison with some other pyridazinoindolones recently described by us and with pyrazoloquinoline (PQ) analogues. An anticonvulsant activity greater than PQs was generally observed for PIs. Notably, in the test of audiogenically induced seizures, one compound showed a potency comparable to that of diazepam.     

Structure-activity relationships of novel anti-malarial agents. Part 2: cinnamic acid derivatives

We have described compound 1 as a lead structure for a novel class of anti-malarial agents. Replacement of the 3-phenylpropionyl moiety of the lead structure 1 by a 4-propoxycinnamic acid residue resulted in a significant improvement in antimalarial activity. Compound 3q represents an important step in the development of lead structure 1 into an anti-malarial drug candidate.     

Structure-activity relationships of novel anti-malarial agents. Part 3: N-(4-acylamino-3-benzoylphenyl)-4-propoxycinnamic acid amides

We have described 5-(4-propoxycinnamoylamino)-2-(4-tolylacetylamino)benzophenone 6e as a novel lead for anti-malarial agents. Anti-malarial activity of these 5-(4-propoxycinnamoylamino)benzophenones proved to be quite sensitive against variations of the acyl substituent at the 2-amino group. Best activity was obtained with phenylacetic acid moieties carrying small substituents in the para-position. From the para-substituents evaluated, the trifluoromethyl group yielded the most active compound (6j) in this series (IC50=120 nM). Deviations from the phenylacetic acid substructure, shifting the substituent into the ortho-position or bulkier para-substituents resulted in a significant reduction in anti-malarial activity.     

Structure-activity relationships of novel anti-malarial agents. Part 4: N-(3-benzoyl-4-tolylacetylaminophenyl)-3-(5-aryl-2-furyl)acrylic acid amides

In a previous report, we have described novel anti-malarial compounds based on a 2,5-diaminobenzophenone scaffold. Here, we have invesigated acryloyl derivatives carrying a biaryl structure consisting of a terminal aryl residue and a central 2-furyl ring. Several compounds were obtained in the series of para-substituted phenylfurylacryloyl derivatives that displayed improved anti-malarial activity in comparison to earlier described derivatives. From the structure-activity relationships it can be deduced that there has to be a lipophilic moiety in the para-position of the terminal phenyl residue. Furthermore, there are indications that, alternatively, activity may benefit from the presence of a polar moiety with hydrogen bond acceptor properties.     

Structure-activity relationships within a series of caspase inhibitors. Part 2: Heterocyclic warheads

Various heterocyclic hetero-methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A study of their structure-activity relationship (SAR) related to caspase-1, -3, -6, and -8 is reported. Their efficacy in a cellular model of cell death is also discussed. Potent broad-spectrum caspase inhibitors have been identified.     

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.     

Estrogen receptor ligands. Part 6: Synthesis and binding affinity of dihydrobenzodithiins

Dihydrobenzodithiin compounds (1-6) were prepared to explore the expansion of the dihydrobenzoxathiin lead compounds I-III as SERAMs (Selective Estrogen Receptor Alpha Modulators). The dihydrobenzodithiin compounds generally maintained a high degree of selectivity for ERalpha over ERbeta, however, they lacked the in vivo antagonism/agonism activity exhibited by the lead class in an immature rat uterine growth model.     

Synthesis and biological evaluation of novel 2-(1H-imidazol-4-yl)cyclopropane carboxylic acids: key intermediates for H3 histamine receptor ligands

A new synthetic methodology to provide cis-2-(1H-imidazol-4-yl)-cyclopropane carboxylic acids is described. These cyclopropanes are useful for the preparation of novel H₃ receptor agents.     

Novel and highly potent histamine H3 receptor ligands. Part 1: withdrawing of hERG activity

Pre-clinical investigation of some aryl-piperidinyl ether histamine H3 receptor antagonists revealed a strong hERG binding. To overcome this issue, we have developed a QSAR model specially dedicated to H3 receptor ligands. This model was designed to be directly applicable in medicinal chemistry with no need of molecular modeling. The resulting recursive partitioning trees are robust (80-85% accuracy), but also simple and comprehensible. A novel promising lead emerged from our work and the structure-activity relationships are presented.     

Synthesis and structure-activity relationships of 4-hydroxy-4-phenylpiperidines as nociceptin receptor ligands: Part 2

A series of 4-[2-(aminomethyl)phenyl]-1-[bis(2-chlorophenyl)methyl]-4-hydroxypiperidine analogs has been identified as nociceptin receptor ligands. These compounds display high affinity and functional activity at the nociceptin receptor. The synthesis and structure-activity relationships at the C-4 phenyl and N-1 positions are described and the antitussive activity of a selected compound is reported.