Imidazopyrimidine

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Colin R. Gardner - One of the best experts on this subject based on the ideXlab platform.

  • General approach leading to the development of imidazoquinoline and Imidazopyrimidine benzodiazepine receptor ligands
    Drug Development Research, 1991
    Co-Authors: W. Roger Tully, Colin R. Gardner, Robert Westwood
    Abstract:

    The observation that the imidazoquinoxaline ethyl ester RU32180 possessed an affinity of 175 nM for benzodiazepine (BDZ) receptors led to the discovery of several series of potent receptor ligands such as esters ofimidazoquinolines and imidazobenzothiazoles. The lack of oral activity shown by these esters was rectified in the benzoyl imidazoquinolne RU31719, which possessed nearly all the properties of a classical BDZ agonist but with reduced muscle relaxant activity. Structure-activity studies led to the benzoyl imidazoquinazoline RU32514 and from there to the Imidazopyrimidine RU32698, which has robust anxiolytic activity, but induces little sedation and no muscle relaxation in a range of animal models. Further studies yielded the oxadiazolyl Imidazopyrimidines such as RU33203, a potent partial agonist, and the thiazolyl Imidazopyrimidine RU33356, the first member of the series to possess antagonist/inverse agonist properties.

  • relationship between structure and efficacy at central benzodiazepine receptors for a series of Imidazopyrimidines and imidazoquinolines
    Drug Development Research, 1991
    Co-Authors: Colin R. Gardner, Paula Budhram, Robert M. J. Deacon, Andrew T Thomson
    Abstract:

    The efficacy of a series of novel imidazoquinolines and Imidazopyrimidines at benzodiazepine (BDZ) receptors was assessed using in vivo models: food-motivated conflict in rats, stress-induced ultrasounds in rat pups, leptazol seizures in mice, and suprahyoid muscle twitching in urethane-anaesthetized rats. Compounds showing activities similar to classical BDZs (anxiolytic, anticonvulsant, and central nervous system (CNS) depressant activities, as well as depression of twitching) have been classified as strong agonists while those showing reduced CNS depressant effects, or reduced anticonvulsant effects with an antagonist profile in twitching, have been classified as moderate and weak partial agonists, respectively. Compounds were regarded as weak or strong inverse agonists according to their abilities to potentiate both seizures and twitching at doses which antagonize full BDZ agonists in the models of anxiety. Modification of two regions of these molecules caused changes in their efficacies. Agonist efficacy following modification to position 2 gave the ranking: oxadiazole > benzoyl > > cyclopropyl ketone ≧ thiazole with the latter compounds becoming inverse agonists in some cases, depending on other changes to the structure. The imidazoquinolines were stronger agonists than the Imidazopyrimidines. As the 5,6-substitutions on the Imidazopyrimidines were reduced, compounds possessed less agonism and more inverse agonism, giving the agonism ranking 5-methyl, 6-allyl > 5-methyl, 6-ethyl > 5,6-tetramethylene > 5-ethyl,6-H ≧ 5-methyl,6-H. Combination of the effects of modification of these two regions of the molecules has yielded a scheme which predicts the efficacy of individual members of the series. This scheme has been used to design other molecules with specific efficacies for BDZ receptors in this and other chemical series.

  • effects of selected Imidazopyrimidine ligands for benzodiazepine receptors in rodent models of anxiety and behavioural impairment
    Drug Development Research, 1991
    Co-Authors: Robert M. J. Deacon, Andrew P Guy, Colin R. Gardner
    Abstract:

    A group of Imidazopyrimidine ligands of benzodiazepine receptors has been shown to produce anti-conflict effects in a punished rat operant task, at comparable doses to classical benzodiazepine agonists such as diazepam. Most were able to attenuate the convulsant effects of pentylenetetrazole and electroshock in the mouse, although with reduced potency compared with the reference classical benzodiazepines. Their activity in tests of functional central nervous system impairment (rotating drum and potentiation of phenobarbitone in the mouse, potentiation of chloral hydrate and pull-up test in the rat) was also markedly less than the classical agonists. These data are consistent with these Imidazopyrimidines being partial agonists at the benzodiazepine receptor.

  • reversal of stress induced arousal in sleeping rats by some Imidazopyrimidine benzodiazepine receptor ligands
    Drug Development Research, 1991
    Co-Authors: Vernon James, Colin R. Gardner
    Abstract:

    Five selected Imidazopyrimidine ligands for benzodiazepine receptors which show nonsedative anxiolytic behavioral profiles, were tested for their ability to reverse arousal induced by intermittent footshock stress in sleeping rats. RU32698, RU32759, RU33203, and RU33543 showed dose-related inhibition of stress-induced arousal in the dose range 2–10 mg/kg orally, as did chlordiazepoxide. After 14 daily doses there was little or no decrease in the magnitude of this effect with RU32759 and RU32698, respectively. In contrast, RU32514 only weakly reversed stress-induced arousal at 10 mg/kg, a dose which is maximally active in a conflict procedure in rats. It is suggested that RU32514 possesses only weak agonist activity at benzodiazepine receptors and this is insufficient for it to be effective in this test. RU32698 and RU32759 show potential for development as non-sedative anxiolytics and the sub-acute dosing experiment suggests that they may not show marked tolerance.

John R Atack - One of the best experts on this subject based on the ideXlab platform.

  • gabaa receptor subtype selective modulators i α2 α3 selective agonists as non sedating anxiolytics
    Current Topics in Medicinal Chemistry, 2011
    Co-Authors: John R Atack
    Abstract:

    The prototypic benzodiazepines, such as diazepam, are not only anxiolytic but also produce sedation. These effects are mediated by GABA(A) receptors containing either an α1, α2, α3 or α5 subunit at which the positive modulatory effects (i.e., agonist efficacy) of benzodiazepines are mediated via a specific benzodiazepine recognition site. Recent molecular genetic and pharmacological data point to α1-containing GABA(A) receptors as the "sedative" and α2- and/or α3-containing receptors as the "anxiolytic" subtype(s). Therefore, at Merck Sharp & Dohme attempts were made to identify subtype-selective compounds that modulate α2/α3 but not α1 receptor function with the prediction that such compounds would be non-sedating anxiolytics. The initial strategy for discovering such "anxioselective" compounds focussed on producing compounds with much higher affinity at the α2/α3 compared to α1 subtypes. The starting point for this approach was the triazolophthalazine series developed from a combination of a screening hit and a literature compound [1]. However, the maximum α3 versus α1 binding selectivity that could be achieved in this series was 12-fold and this was not considered sufficient for an appropriate in vivo pharmacological differentiation compared to non-selective compounds. Nevertheless, within this series compounds demonstrating (albeit to a limited extent) higher agonist efficacy at the α3 versus α1 subtype were also identified. This suggested that it might be possible to synthesize a compound with higher efficacy at the α2 and/or α3 compared to α1 subtypes, ideally with no efficacy at the latter subtype (i.e., a compound with subtype-selective efficacy). By changing the structure from a triazolophthalazine to a triazolopyridazine core, a number of either pharmacological tool compounds (L-838417, MRK-067 and MRK-696) or clinical development candidates (MRK-409 and TPA023) were identified. Encouraged by the success of this approach and the observation that the benzimidazole NS-2710 had a modest degree of α3 versus α1 selectivity efficacy, a structurally-related class of imidazopyridines was also explored. The introduction of an additional nitrogen into the imidazopyridine core gave the Imidazopyrimidine series which initially had issues with poor dog pharmacokinetics. However, this was resolved and resulted in the identification of the development candidates MRK-623 and MRK-898. A fluoroimidazopyridine was found to be a bioisostere of the Imidazopyrimidine core and in this series the α3-selective tool compound TP003 was identified. The addition of a further nitrogen into the Imidazopyrimidine core produced the imidazotriazine series, which yielded the clinical candidate TPA023B. Imidazopyrazinone and imidazotriazinone compounds offered no advantages over their respective Imidazopyrimidine and imidazotriazine analogues. Additional pharmacological tool compounds were identified within the pyridine, pyrazolotriazine, pyridazine and pyrazolopyridone series highlighting the general feasibility of GABA(A) receptor subtype selective efficacy as a strategy for developing compounds with novel in vitro and in vivo profiles.

Raed A Alqawasmeh - One of the best experts on this subject based on the ideXlab platform.

  • post groebke blackburn multicomponent protocol synthesis of new polyfunctional imidazo 1 2 a pyridine and imidazo 1 2 a pyrimidine derivatives as potential antimicrobial agents
    European Journal of Medicinal Chemistry, 2010
    Co-Authors: Taleb H Altel, Raed A Alqawasmeh
    Abstract:

    New antimicrobial agents [imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine] have been synthesized. Their antimicrobial activities were conducted against various Gram-positive and Gram-negative bacteria including Staphylococcus aureus. Compounds 5d, 7a, 10a, 11a and 12a proved to efficiently inhibit the growth of all the Gram-positive and Gram-negative strains investigated. Results of this study showed that the nature of the substituents on the armed phenyl groups determined the extent of the activity of the fused imidazopyridine and/or Imidazopyrimidine derivatives. Preliminary structure-activity observations revealed that groups with positive sigma and positive bi values (e.g. 5d, 6c, 12a, 12d) were significantly more active compared to other bioisosteres (e.g. 5b). Furthermore, increasing the molar refractivity of the substitution pattern (e.g. 5b, 6b and 6d) sharply decreased the antibacterial activity.

Huanfeng Jiang - One of the best experts on this subject based on the ideXlab platform.

Liso G - One of the best experts on this subject based on the ideXlab platform.

  • N-Benzyl-2-(6,8-dichloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-N-(6- (7-nitrobenzo[c][1,2,5]oxadiazol-4-ylamino)hexyl)acetamide as a New Fluorescent Probe for Peripheral Benzodiazepine Receptor and Microglial Cell Visualization
    'American Chemical Society (ACS)', 2007
    Co-Authors: Denora N, Lopedota A, Suzuki H, Sawada M, Serra M, Biggio G, Latrofa A, Trapani G, Liso G
    Abstract:

    The aim of this work was to develop new fluorescent probes for the localization and function of the peripheral benzodiazepine receptor (PBR). This receptor is primarily expressed on the mitochondria, and it is overexpressed in a variety of different states including glioma, breast cancer, Alzeheimer’s disease, and activated microglia. For the mentioned purpose, imidazopyridine and Imidazopyrimidine compounds 5-20 were synthesized, and their affinity for PBR was determined. Although some intrinsically fluorescent Imidazopyrimidine compounds 12-20 possess good binding affinity, they cannot be used for visualizing PBR due to their unfavorable fluorescence characteristics. Among the imidazopyridine-7-nitrofurazan conjugates 5-11, compound 10 was the most active, and it was found to stain live Ra2 microglial cells effectively. An in vivo biodistribution study carried out on compound 10 showed that this imidazopyridine derivative, injected in the carotid artery, is able to penetrate to liver parenchyma, whereas fluorescein isothiocyanate labeled dextran (FITC-dextran), used as a control dye, hardly penetrated from blood vessels to tissues. On the other hand, as for the distribution to brain, the patterns of staining with 10 and FITC-dextran are similar, indicating that both of them hardly penetrate into the brain because of the existence of the blood-brain barrier. The obtained results indicate that compound 10 represents a new useful fluorescent probe for visualization of activated microglia and PBR

  • N-benzyl-2-(6,8-dichloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl)-N(6-(7-nitrobenzo[c][1,2,5]oxadiazol-4-ylamino)hexyl)acetamide as a new fluorescentprobe for peripheral benzodiazepine receptor and microglialcell visualization
    'American Chemical Society (ACS)', 2007
    Co-Authors: Denora N, Lopedota A, Suzuki H, Sawada M, Serra M, Biggio G, Latrofa A, Trapani G, Liso G
    Abstract:

    The aim of this work was to develop new fluorescent probes for the localization and function of the peripheral benzodiazepine receptor (PBR). This receptor is primarily expressed on the mitochondria, and it is overexpressed in a variety of different states including glioma, breast cancer, Alzeheimer's disease, and activated microglia. For the mentioned purpose, imidazopyridine and Imidazopyrimidine compounds 5-20 were synthesized, and their affinity for PBR was determined. Although some intrinsically fluorescent Imidazopyrimidine compounds 12-20 possess good binding affinity, they cannot be used for visualizing PBR due to their unfavorable fluorescence characteristics. Among the imidazopyridine-7-nitrofurazan conjugates 5-11, compound 10 was the most active, and it was found to stain live Ra2 microglial cells effectively. An in vivo biodistribution study carried out on compound 10 showed that this imidazopyridine derivative, injected in the carotid artery, is able to penetrate to liver parenchyma, whereas fluorescein isothiocyanate labeled dextran (FITC-dextran), used as a control dye, hardly penetrated from blood vessels to tissues. On the other hand, as for the distribution to brain, the patterns of staining with 10 and FITC-dextran are similar, indicating that both of them hardly penetrate into the brain because of the existence of the blood-brain barrier. The obtained results indicate that compound 10 represents a new useful fluorescent probe for visualization of activated microglia and PBR