N^G‐Acylated Aminothiazolylpropylguanidines as Potent and Selective Histamine H₂ Receptor Agonists

Abstract

The bioisosteric replacement of the guanidino group in arpromidine-like histamine H(2) receptor (H(2)R) agonists by an acylguanidine moiety is a useful approach to obtain potent H(2)R agonists with improved oral bioavailability and blood-brain barrier penetration. Unfortunately, the selectivity of such N(G)-acylated imidazolylpropylguanidines for the H(2)R is poor, in particular versus histamine H(3) (H(3)R) and H(4) receptors (H(4)R). This drawback appears to depend on the "privileged" imidazolylpropylguanidine structure. The 2-amino-4-methylthiazol-5-yl moiety is a bioisostere of the imidazole ring in the moderately potent H(2)R-selective histamine analogue amthamine. This approach was successfully applied to acylguanidine-type H(2)R agonists. The aminothiazoles are nearly equipotent to the corresponding imidazoles as H(2)R agonists. Compared with histamine, the potency is increased up to 40-fold on the guinea pig right atrium, and up to 125- and 280-fold in GTPase assays with human and guinea pig H(2)R-G(salphaS) fusion proteins expressed in Sf9 insect cells, respectively. Docking studies on H(2)R models support the hypothesis that 2-aminothiazolyl and imidazolyl derivatives interact with H(2)Rs as bioisosteres. In contrast to the imidazoles, the aminothiazoles are devoid of agonistic or relevant antagonistic effects on H(1), H(3), and H(4) receptors. Moreover, unlike amthamine, the 4-methyl group does not significantly contribute to the H(2)R agonism of N(G)-acylated 2-amino-4-methylthiazol-5-ylpropylguanidines.

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

“…[14,16] N'-Substituted N-tert-butoxycarbonyl-S-methylisothioureas 16-27: DIPEA (4.0 mmol) in CH 2 Cl 2 (10 mL) was added to a solution of N-tert-butoxycarbonyl-S-methylisothiourea (0.76 g, 4.0 mmol) in 10 mL anhydrous CH 2 Cl 2 . A solution of the respective acylating agent (4.0 mmol) in CH 2 Cl 2 (5 mL) was added, and the reaction mixture was shaken overnight.…”

“…[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.…”

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

“…The selectivity problem was solved by bioisosteric replacement of the imidazol-4-yl with a 2-aminothiazol-5-yl residue, optionally bearing a 4-methyl substituent as in amthamine. 2-Aminothiazoles, such as UR-BIT24, are about equipotent to the corresponding imidazoles at the H 2 receptor but devoid of noteworthy activities at H 1 receptors, H 3 receptors and H 4 receptors (Kraus et al, 2009).…”

[3H]UR‐DE257: Development of a Tritium‐Labeled Squaramide‐Type Selective Histamine H2 Receptor Antagonist

“…The K d value determined from saturation binding was applied for the calculation of K i values by means of the Cheng-Prusoff equation. [45] As summarized in Table 5, the hH 2 R binding affinity of the agonists histamine (K i = 534 nm), amthamine (K i = 244 nm), URBit24 [46] (K i = 7.1 nm) and UR-AK480 [47] (K i = 1.9 nm), and of the antagonists famotidine (K i = 136 nm), ranitidine (K i = 1730 nm), BMY 25368 (K i = 19 nm) and iodoaminopotentidine (K i = 0.31 nm) were consistent with reported data from functional and binding experiments. [40,48] The K i value of 24 a on the hH 2 R (28 nm), determined by competition binding experiments with the labeled analogue 24 b, corresponds very well to the K d value of compound 24 b (31 nm), and the data for the rat and guinea H 2 R species orthologues were in the same range (K i values: 16 and 43 nm, respectively).…”