Structure−Activity Studies on a Series of a 2-Aminopyrimidine-Containing Histamine H<sub>4</sub> Receptor Ligands

Altenbach, Robert J.; Adair, Ronald M.; Bettencourt, Brian M.; Black, Lawrence A.; Fix-Stenzel, Shannon R.; Gopalakrishnan, Sujatha M.; Hsieh, Gin C.; Liu, Huaqing; Marsh, Kennan C.; McPherson, Michael J.; Milicic, Ivan; Miller, Thomas R.; Vortherms, Timothy A.; Warrior, Usha; Wetter, J.; Wishart, Neil; Witte, David G.; Honoré, Prisca; Esbenshade, Timothy A.; Hancock, Arthur A.; Brioni, Jorge D.; Cowart, Marlon

doi:10.1021/jm8005959

Cited by 64 publications

(71 citation statements)

References 39 publications

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“…Dual activation of H 1 receptor and H 4 receptor on sensory neurons, which in turn results in the excitation of histamine-sensitive afferents, may underlie the sensation of itch (Rossbach et al, 2011). These effects may translate into the nociceptive and antipruritic activities seen in animal models (Bell et al, 2004;Coruzzi et al, 2007;Dunford et al, 2007;Altenbach et al, 2008;Cowart et al, 2008;Nakano et al, 2009;Rossbach et al, 2009;Yamaura et al, 2009;Cowden et al, 2010b;Hsieh et al, 2010a,b). In both cases the effects of H 4 receptor antagonists appear to be mediated via modulation of neuronal activity.…”

Section: Functionmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

et al. 2015

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Section: Functionmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

et al. 2015

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“…The structure-activity relationship (SAR) was thoroughly investigated for a large series of 2-aminopyrimidines as H4 histamine hormone receptor ligands [46]. The reference drug was 4-tert-butyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-ylamine 54a.…”

Section: -Aminopyrimidine Derivatives As H4 Hormone Receptor Ligandsmentioning

confidence: 99%

Biological Activity of Adamantane-Containing Mono- and Polycyclic Pyrimidine Derivatives* (A Review)

Shokova

Ковалев

2016

Pharm Chem J

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Biological test results for a series of adamantane-containing pyrimidines, purines, and their derivatives that were synthesized and studied in 1999 -2001 are reviewed. Pyrimidine, purine, and similar scaffolds are exceedingly common key building blocks in the design of drugs with the broadest spectra of action comprising antibacterial, antiviral, antitumor, neurotropic, antifungal, immunotropic, and other types of drugs. An adamantane moiety in the molecules often has a substantial effect on the biological properties. Practically all studies included in the first part of the present review [1] explain their goals using just such factors. Therefore, almost every study consisted of two parts, i.e., chemical and biological.The previous studies focused on synthetic pyrimidine derivatives such as monocyclic pyrimidines (pyrimidinone, uracil, cytosine, uridines, etc.), condensed di-and polycyclic compounds (pyrazolopyrimidine, triazolopurine, xanthene, etc.), and adenosines with various substitution patterns and types of substituents. An adamantane moiety could be either bonded directly to the heterocycle or on its periphery. This part of the review focuses on biological tests of the synthesized compounds**. The subsections present research results according to individual type of biological activity. In addition, a subsection called Biological Screening was included. It includes results for instances where the activity of certain rather large groups (types) of compounds was studied for several rather than a single indication. This was most often related to characteristic antimicrobial, fungicidal, and antimalarial activity and the cytotoxicity of the drugs. In most instances, we considered it counterproductive to lump these results into piles in various sections. * Part 1 of the present review [1] contains information regarding the synthesis of adamantane-containing pyrimidine derivatives. ** The following terms [abbreviation and its explanation (if it exists) given in the corresponding publication] are used to present the biological test results:MIC, minimum inhibiting concentration [2, 3, 6]. MIC 50 , minimum inhibiting concentration suppressing development of virus-induced cytopathic activity by 50% [23,51]. MCC 50 , minimum cytotoxic concentration causing 50% inhibition of cell growth (VERO cells) [23,51]. CD 50 , cytotoxic dose causing 50% inhibition of cell growth [28]. CC 50 , cytotoxic concentration of a drug required to inhibit 50% of any subject in vitro [3,22]. EC 50 , 50% effective plasma concentration at which the effectiveness is 50% of the maximum for this drug in vivo [3,7,9,22]. ID, inhibiting dose; IC, inhibiting concentration, IC 50 , [5,6,9,10,41]; ID 80 , [3]; ID 95 , [28]. SI, selectivity index; SI = MCC 50 /MIC 50 [23, 51]; SI = CC 50 /EC 50 [3, 22]; SI = CD 50 /ID 50 [28]. pEC 50 , negative logarithm of EC 50 [46]. K i , equilibrium dissociation constant [42, 44, 45].

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“…The screen used a fluorimetric imaging plate reader (FLIPR) assay that measured changes in intracellular calcium to detect H 4 stimulation in a HEK-293 cell line stably expressing the human or rat H 4 receptor. 18 Screening hit 6 ( Figure 4) was selected as a lead on the basis of its structural novelty and moderately potent human H 4 binding affinity. The low rat affinity of 6 was identified as an essential parameter for optimization to support profiling in rodent disease models.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Functional Profiling of 2-Aminopyrimidine Histamine H₄ Receptor Modulators

et al. 2015

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Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This review provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis.

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Structure−Activity Studies on a Series of a 2-Aminopyrimidine-Containing Histamine H₄ Receptor Ligands

Cited by 64 publications

References 39 publications

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

Biological Activity of Adamantane-Containing Mono- and Polycyclic Pyrimidine Derivatives* (A Review)

Functional Profiling of 2-Aminopyrimidine Histamine H₄ Receptor Modulators

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Structure−Activity Studies on a Series of a 2-Aminopyrimidine-Containing Histamine H4 Receptor Ligands

Cited by 64 publications

References 39 publications

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

Biological Activity of Adamantane-Containing Mono- and Polycyclic Pyrimidine Derivatives* (A Review)

Functional Profiling of 2-Aminopyrimidine Histamine H4 Receptor Modulators

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Structure−Activity Studies on a Series of a 2-Aminopyrimidine-Containing Histamine H₄ Receptor Ligands

Functional Profiling of 2-Aminopyrimidine Histamine H₄ Receptor Modulators