Ming-Qiang Zhang

Structure-activity relationships within a series of analogues of the histamine H1-antagonist terfenadine

Abstract A number of terfenadine derivatives including terfenadine enantiomers were synthesized and tested for histamine H 1 -receptor affinity. No significant differences in H 1 activity were found between terfenadine enantiomers. Qualitative structure-activity relationship studies identified the α,α-diphenyl-4-piperidinomethanol moiety as the pharmacophore for the H 1 activity of this group of compounds. The major role of the phenylbutanol moiety in terfenadine seems to be preventing the compound from crossing the blood-brain barrier.

Synthesis and pharmacological evaluation of some amino-acid-containing cyproheptadine derivatives as dual antagonists of histamine H1- and leukotriene D4-receptors

Summary A novel series of cyproheptadine derivatives, in which an amino acid or a dipeptide moiety was introduced at the piperidine nitrogen, have been synthesized. The amino acid and dipeptide moieties were taken as part of leukotriene D 4 (LTD 4 ) pharmacophore. This modification reduced the H 1 -antihistamine activity (100–1000-fold) but elevated the anti-LTD 4 activity (10–100-fold) of the compounds, as compared with cyproheptadine. As a result, some of the new compounds, especially the α-aminopropionic acid derivatives 4 , are well-balanced dual antagonists of histamine and LTD 4 with both activities at micromolar range. Radioligand binding studies have confirmed that the new compounds, but not cyproheptadine for LTD 4 , exert their action through competetive occupation of the receptors. One compound, (S)-2-benzyloxycarbonyl-amino-3-[4-(10,11-dihydro-5 H -dibenzo[ a,d ]cyclohepten-5-yloxy)piperidin-1-yl]propionic acid (4c) , was tested in an in vitro guinea-pig asthma model. It exhibits much more potent inhibition (ICS 50 = 1.5 μM) against antigen-induced contraction than either terfenadine or FPL55712, the reference drugs. As indicated by an ex vivo binding assay, the drug 4c does not readily pass the blood-brain barrier, and therefore is unlikely to cause sedating side-effects at a therapeutic dose.

Histamine H1 receptor ligands. Part I. Novel thiazol-4-ylethanamine derivatives: synthesis and in vitro pharmacology.

A series of 2-substituted thiazol-4-ylethanamines have been synthesized and tested for their histaminergic H1-receptor activities. The compounds with 2-phenyl substitution, regardless of the different physicochemical properties of the meta-substituents at the phenyl ring, showed weak H1-agonistic activity with pD2 values ranging from 4.35 to 5.36. When the phenyl group was replaced by a benzyl group, the resulting compounds all exhibited weak H1-antagonistic activity (pA2: 4.14-4.82).

Calcium antagonism and structure-affinity relationships of terfenadine, a histamine H1 antagonist, and some related compounds

Abstract— Calcium channel affinity of terfenadine and its optical isomers was determined by the displacement of [3H]nitrendipine on rat cerebral cortex membranes. Terfenadine showed a pKd of 6·36±0·03 whereas its R(+)‐isomer (VUF4567) had a pKd value of 6·39±0·03 and the S(–)‐isomer (VUF4568) had a pKd of 6·40 ± 0·04. The same affinity between the enantiomers suggests that the binding domain on the membrane is not sterically restricted towards the part of the molecule in which the chiral centre is present. The characteristics of terfenadine in regulating [3H]nitrendipine binding were similar to those of some other diphenyl‐alkylamine type calcium antagonists. It allosterically altered the binding affinity for nitrendipine and acted at the same site linked to the calcium channel as gallopamil. A structure‐affinity relationship among a group of terfenadine analogues is discussed.

Synthesis of carboxylated flavonoids as new leads for LTD4 antagonists

Summary A series of 3′- and 5′-carboxylated chalcones, 6- or 8-carboxylated flavones and 6-carboxylated flavanones, -flavanols and -flavans were prepared. The compounds were tested for their inhibitory activities against leukotriene D 4 (LTD 4 ) induced contraction of guinea-pig ileum. A new and convenient synthetic route to 3-acetyl-2-hydroxybenzoic acid ( 1d ), a key intermediate for the synthesis of 3′-carboxy-2′-hydroxychalcones and 8-carboxylated flavones, was developed. The activities of the tested compounds ranged from 0 to 63% inhibition at 10 −5 M drug concentration against a single challenge of 10 −8 M LTD 4 . Several compounds were tested in a radioligand binding assay against [ 3 H]LTD 4 on guinea-pig lung membrane. The quinoline-containing chalcone 12 and flavone 17 were found to exhibit significant but weak affinities for LTD 4 receptors with p K D -values of 4.95 and 4.83, respectively, and are interesting lead structures for the development of rigid LTD 4 antagonists. In contrast, the rest of the compounds tested in the binding assay did not show significant displacement of the radioligand, implying that for these compounds the functional activity is probably not caused by competitive antagonism at the LTD 4 receptor. The exact mechanism of the relaxant activity remains unclear.

Optical isomers of the H1 antihistamine terfenadine: synthesis and activity

Abstract The optical isomers of the H1 antagonist terfenadine, VUF4567 and VUF4568, were synthesized in excellent enantiomer excess. No significant difference in their affinity for histamine receptors in both central (guinea-pig cerebellum) and peripheral (guinea-pig ileum) tissue was found between the R and S isomers.

Histamine H1 receptor ligands. Part II. Synthesis and in vitro pharmacology of 2-[2-(phenylamino)thiazol-4-yl]ethanamine and 2-(2-benzhydrylthiazol-4-yl)ethanamine derivatives

New 2-[2-(phenylamino)thiazol-4-yl]ethanamine and 2-(2-benzhydrylthiazol-4-yl)ethanamine derivatives were prepared and tested in vitro as H1 receptor antagonists. The compounds with 2-phenylamino substitution with meta-halide substituents at the phenyl ring, showed weak H1-antagonistic activity (pA2: 4.62-5.04) and this activity was completely lost in the case of meta-methyl substituent (pA2 < 4). When the phenylamino group was replaced by benzhydryl groups of classic antihistamines, the resulting compounds exhibited slightly improved H1-antagonistic activity (at the meta-position pA2: 6.38-6.15; at the para-position pA2: 6.04-5.87).

The role of arginine in the binding of LTD4 antagonists to cysLT1 receptors of guinea pig lung

Abstract Using the chemical masking agent phenylglyoxal, we have selectively blocked the arginine residues in leukotriene cysLT1 receptors of guinea pig lung preparations. This treatment resulted in the markedly decreased affinity of LTD4 antagonists to the receptor without affecting the affinity of LTD4 itself. Our results indicate that LTD4 and its antagonists may have different modes of interaction with the cysLT1 receptor.

Terfenadine: A mixture of equipotent antihistamine enantiomers without a clear ‘isomeric ballast’

Terfenadine was the first non-sedating histamine H1 receptor antagonist and one of the most frequently prescribed H1 antihistamines. Terfenadine has one asymmetric centre in the molecule and is currently used as a racemate. Different methods and approaches for obtaining pure enantiomers of terfenadine are summarized and discussed in the present paper. Studies on antihistamine activity of the enantiomers, their side-effects on the central nervous system, calcium channel affinity and metabolism are also reviewed and analysed.

Chiral manipulation of drug selectivity: Studies on a series of terfenadine-derived dual antagonists on H1-receptors and calcium channels

A series of terfenadine derivatives were evaluated for enantioselectivity on histamine H1-receptors and calcium channels. Whereas H1-receptors are only sterically discriminative against the benzhydryl part of the molecules, calcium channels showed enantioselectivity to either the phenylbutyl part or the benzhydryl part provided that an appropriate lipophilicity is preserved at the chiral site. It is speculated that the hydrophilicity of the butanol moiety is responsible for the lack of stereoselectivity of terfenadine enantiomers since it drives the side chain out the stereoselective site of calcium channels, which are lipophilic. In four different test systems, (guinea-pig ileum, guinea-pig lung membranes, rat aorta and rat cortex mebranes), this series of compounds generally showed about 10 times higher activity on H1-receptors than on calcium channels. By introducing a chiral center in the different parts of the molecule we were able to increase the selectivity of an enantiomer VUF4648 to calcium channels.