Arpromidine-related acylguanidines: synthesis and structure-activity relationships of a new class of guanidine-type histamine H2 receptor agonists with reduced basicity

There has been increasing evidence that histamine receptor stimulation might be an interesting aspect for the development of future drugs as well. Arpromidine and related imidazolylpropylguanidines are the most potent H2R agonists on the isolated guinea pig right atrium. The strongly basic guanidino group is essential for the agonistic activity but it is also responsible for very low oral bioavailability, non-H2R-mediated effects and lack of penetration across the blood-brain barrier. Therefore, the objective of this work was to design, synthesize and characterize histamine H2 receptor agonists, structurally related to arpromidine, but with lower basicity in order to achieve more favourable pharmacokinetic properties, in particular, oral bioavailability and penetration across the blood-brain barrier. The first part of this project was to develop a general synthetic route for the synthesis of NG-acylated imidazolylpropylguanidines. In Chapter 3, the development of a very convenient and straight forward synthetic route is described for the synthesis of NG-acylated guanidines, from the commercially available starting material, urocanic acid and guanidine, followed by coupling of acids. Then the synthesised compounds were pharmacologically tested on isolated guinea pig tissues (ileum: H1R, H3R; right atrium: H2R), on human H1R expressing cells (U373MG) and on membrane preparations of guinea pig and human histamine H2 or H4 receptor expressing Sf9 cells. The basicity of the acylguanidines is by 4-5 orders of magnitude lower than that of the corresponding guanidines. Acyl and alkyl guanidines are about equipotent as, for instance, demonstrated for the diphenylpropyl versus the diphenylpropanoyl and for impromidine versus the oxo-substituted analogue. Surprisingly, compounds with only one phenyl ring are equally or even more potent than the diaryl analogues. On the isolated guinea pig right atrium the most active H2R agonist, the 3-phenylbutanoyl substituted guanidine was about 30 times more potent than the natural ligand. However, the acylated imidazolylpropylguanidines are superior with respect to pharmacokinetic properties. A very important finding is that the compounds are absorbed from the gastrointestinal tract and are capable of penetrating through the blood-brain barrier. Centrally active H2R agonists will be useful pharmacological tools to study the role histamine H2 receptors in the brain. In Chapter 4, the bioisosteric replacement of the imidazolyl moiety in NG-acylated guanidine-type histamine H2 receptor agonists by a 2-amino-4-methylthiazol-5-yl group resulted in about the same H2R agonistic potency on the isolated guinea pig right atrium as well as in GTPase assays. Interestingly, in the GTPase assay on the human H2R the thiazolyl analogue with cyclohexylbutanoyl substituent was favoured compared to the corresponding phenylbutanoylguanidine. This may be interpreted a hint that a certain degree of selectivity for the human H2R may be achieved by structural variation of both the acyl and the heterocyclylpropyl group. Moreover, the aminothiazoles proved to be devoid of H3R antagonistic activity. Thus, the selectivity for H2R versus H3R can be considerably improved. In Chapter 5, the stereoselective preparation of enantiomers of several chiral new H2R agonists is described. The building block (R and S)-3-phenylbutanoic acid was synthesized from the achiral precursor, methyl (E)-but-2-enoate, via asymmetric conjugate addition of phenylboronic acid by using a catalytic amount of rhodium catalyst and chiral binap ligand, followed by hydrolysis of the methyl ester. The corresponding chiral pyridyl acids with high ee (95-99 %), were prepared by the lipase catalysed enantioselective acetylation of racemic 1-(2-pyridyl)ethanol, followed by SN2 displacement with sodium salt of dimethyl malonate, and finally the decarboxylation of saponified product. Interestingly, the preferred stereoisomers were conversely configured in case of the imidazolyl compound (R > S) and its aminothiazolyl analogue (S > R), respectively. This information is of particular interest with respect to the further refinement of receptor models, as the binding mode of imidazoles and aminothiazoles appears to be different. Meanwhile imidazolylpropylguanidines and corresponding acylated analogues were found to be useful building blocks beyond the preparation of H2R agonists, for instance for the synthesis of ligands preferentially binding to other histamine receptor subtypes, to neuropeptide Y Y1 or Y4 receptors. Thus, there is increasing evidence that in terms of medicinal chemistry the imidazolylpropylguanidine moiety and the acylated analogues may be considered �privileged structures�. An extremely promising perspective results from very recent studies: surprisingly, some of the acylguanidines proved to be rather potent as either agonists or inverse agonists at the recently discovered H4R