Stereochemical Diversity-Oriented Conformational Restriction Strategy. Development of Potent Histamine H₃and/or H₄Receptor Antagonists with an Imidazolylcyclopropane Structure

Abstract

The stereochemical diversity-oriented conformational restriction strategy can be an efficient method for developing specific ligands for drug target proteins, especially in cases where neither the bioactive conformation nor the pharmacophore is known. To develop potent H3 and H4 receptor antagonists, a series of conformationally restricted analogues of histamine with a chiral cis- or trans-cyclopropane structure were designed on the basis of this strategy. These target compounds with stereochemical diversity were synthesized from the versatile chiral cyclopropane units (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (6 and 7, respectively) or their enantiomers ent-6 and ent-7. Pharmacological profiles of these conformationally restricted analogues were shown to be different depending on the cyclopropane backbones. Among the analogues, (1R,2S)-2-[2-(4-chlorobenzylamino)ethyl]-1-(1H-imidazol-4-yl)cyclopropane (11a) with the (1R)-trans-cyclopropane structure has remarkable antagonistic activity to both the H3 (Ki = 8.4 nM) and H4 (Ki = 7.6 nM) receptors. The enantiomer of 11a, i.e., ent-11a, with the (1S)-trans-cyclopropane structure turned out to be a highly potent and selective H3 receptor antagonist with a Ki of 3.6 nM. Conversely, (1R,2R)-2-[(4-chlorobenzylamino)methyl]-1-(1H-imidazol-4-yl)cyclopropane (10a) with the (1R)-trans structure was selective for the H4 receptor (Ki = 118 nM) compared to the H3 receptor (Ki > 10(3) nM). Thus, a variety of compounds with different pharmacological profiles have been developed. These results show that when the structure of the target protein is unknown, the stereochemical diversity-oriented approach can be a powerful strategy in medicinal chemical studies.

Molecular modeling and QSAR-based design of histamine receptor ligands

“…(5) UR-PG80 [50] 5.53 § 7.11* < 5 § < 5 § (6) UR-AK478 [50] < 6 § 7.51* < 5 § 8.07* (7) Thioperamide < 5 < 4 7.3 7.2 (8) JNJ7777120 [70] 6.01 5.07 5.65 7.92 (9) Imidazolylcyclopropane [51] 5.07 ‡ < 5 ‡ 8.07 ‡ 6.07 ‡ (10) Dibenzodiazepine [76] 8.11 5.06 5.04 7.55…”

“…Because of the therapeutic relevance of H 3 R, a lot of studies describing SARs of H 3 receptor ligands are found in literature [51][52][53][54]. To increase understanding of pharmacology of H 3 R ligands on a molecular level, numerous molecular modeling studies were performed.…”

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

“…The pendant pharmacophore groups, the imidazole ring and the hydrophobic 4-chlorobenzyl moiety, are projected in various three dimensional arrangements due to the chiral cis-and transcyclopropane central spacer scaffold. The (1R,2S)-trans-cyclopropane isomer 162 had comparable antagonism of H 3 and H 4 receptors, whereas the (1S,2R)-trans-cyclopropane isomer 163 was a highly selective antagonist for H 3 receptor as shown inFigure 68 201. Therefore, one can achieve receptor subtype potency and selectivity by modifying the molecular configuration at the cyclopropane spacer scaffold.…”

A Library of Conformationally Restricted Saturated Heterocyclic Sulfonyl Chlorides

“…This approach to the design of biologically relevant molecules is referred to as diversity-oriented conformational restriction. 3,4 The idea has been widely used in the design of conformationally restricted amino acids and diamines, 5 whereas conformationally constrained amino sulfonyl chlorides has received much less attention. The limited long-term stability of the latter compounds and some of their derivatives may be one of the reasons for this.…”