Acylguanidines as Bioisosteres of Guanidines: N^G-Acylated Imidazolylpropylguanidines, a New Class of Histamine H₂ Receptor Agonists

Abstract

N1-Aryl(heteroaryl)alkyl-N2-[3-(1H-imidazol-4-yl)propyl]guanidines are potent histamine H2-receptor (H2R) agonists, but their applicability is compromised by the lack of oral bioavailability and CNS penetration. To improve pharmacokinetics, we introduced carbonyl instead of methylene adjacent to the guanidine moiety, decreasing the basicity of the novel H2R agonists by 4-5 orders of magnitude. Some acylguanidines with one phenyl ring were even more potent than their diaryl analogues. As demonstrated by HPLC-MS, the acylguanidines (bioisosteres of the alkylguanidines) were absorbed from the gut of mice and detected in brain. In GTPase assays using recombinant receptors, acylguanidines were more potent at the guinea pig than at the human H2R. At the hH1R and hH3R, the compounds were weak to moderate antagonists or partial agonists. Moreover, potent partial hH4R agonists were identified. Receptor subtype selectivity depends on the imidazolylpropylguanidine moiety (privileged structure), opening an avenue to distinct pharmacological tools including potent H4R agonists.

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

“…Histamine Receptors resulting in substantially reduced basicity (by 4-5 orders of magnitude), but retaining H 2 receptor agonistic activity (Ghorai et al, 2008). Unfortunately, as also found for arpromidine-and impromidine-like compounds, numerous N G -acylated imidazolylpropylguanidines (e.g., UR-AK24) proved to be poorly selective for the H 2 receptor.…”

Application of the Guanidine–Acylguanidine Bioisosteric Approach to Argininamide‐Type NPY Y2 Receptor Antagonists

“…[15] Furthermore, in the field of histamine receptor agonists, acylguanidines were identified as bioisosteres of guanidines or mimics of amino groups. [10,14] Receptor mutagenesis and molecular modeling studies revealed that the guanidino group of the Y 1 R antagonistic (R)-argininamide BIBP3226 and its N G -acylated analogues interact with a highly conserved Asp residue in TM6 of the Y 1 R. [32] In the Y 2 R an Asp residue at the corresponding position is crucial for agonist binding, but does not substantially contribute to binding of BIIE0246. [33,34] Other residues were found to be important for direct antagonist interactions, such as Tyr in TM2 and Leu in TM5.…”

“…Previously, the replacement of guanidine groups with acyl-or carbamoylguanidine moieties proved to be a very successful bioisosteric approach for histamine H 2 , H 3 , and H 4 receptor ligands, [10][11][12][13][14] and for argininamide-type NPY Y 1 R antagonists [15][16][17] derived from BIBP3226 ( Figure 1). The introduction of various electron-withdrawing substituents at the N G -position of BIBP3226 resulted in analogues with similar or even increased Y 1 R antagonistic activities, [16] and opened a route toward fluorescence-labeled [17,18] and tritiated [15] highly potent Y 1 R antagonists.…”

Histamine H4 receptor–RGS fusion proteins expressed in Sf9 insect cells: A sensitive and reliable approach for the functional characterization of histamine H4 receptor ligands

“…Since the hH 4 R-GAIP fusion protein, compared to the standard co-expression system (hH 4 R + G i2 + G 1  2 ), resulted in an increased signal-to-noise ratio with unchanged ligand potencies and efficacies, we decided to use hH 4 R-GAIP (+ G i2 + G 1  2 ) as a standard test system for the characterization of hH 4 R ligands in our medicinal chemistry program [39,40]. M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 20 - Fig.…”