Synthesis and biological evaluation of heteroalicyclic cyanoguanidines at histamine receptors

Recent studies on histamine receptor (HR) subtypes identified imidazolyl butyl cyanoguanidines, like UR‐PI376, as highly potent agonists at the human histamine H₄ receptor (hH₄R). While imidazole‐containing compounds display drawbacks in pharmacokinetics, we studied the possibility of replacing the heteroaromatic cycle by nonaromatic six‐membered heterocycles (piperidine, morpholine, thiomorpholine, and N‐methylpiperazine) as potential bioisosteres. Beyond that, this approach should give more information about the indispensability of the aromatic ring as a basic head group. Besides these changes, a variation of the spacer length (C₃–C₅) connecting the heterocycle and the cyanoguanidine moiety has been made to possibly trigger the selectivity towards the respective HRs. Investigations in radioligand‐binding assays exhibited only very weak activity at the hH₁R and hH₃R, while nearly all compounds were inactive at the hH₂R and hH₄R. In the case of piperidine‐containing compounds, moderate affinities at the hH₃R over the single‐digit micromolar range were detected.     

Potent hypolipidemic activity of mimetic amides of fibrates based on the 2‐methoxy‐4‐(2‐propenyl)phenoxyacetic scaffold

A series of bioisosteric analogues of fibrates, such as clofibrate ( 2 ) and bezafibrate ( 3 ), was designed, considering the pharmacophore potential of phenoxyacetic derivatives 4 related to α‐asarone ( 1 ) in their structure. Thus, the hypolipidemic activity of the series of amides 5a‐5j , 6a‐6d , and 7a‐7c , amines 8b‐8d , and amino acids 9a‐9e has been evaluated. A significant decrease in serum cholesterol was observed in mice for a number of these compounds. Some of them also showed a lowering of low‐density lipoprotein cholesterol, and a few had an effect on increasing the high‐density lipoprotein cholesterol levels, and on reducing the triglyceride serum contents. Phenoxyacetic, phenoxyethyl‐amido and ‐amino moieties, as well as the presence of a chlorine atom in their aromatic rings, were identified as potential pharmacophores. Unexpectedly, derivatives 9a‐9e , bearing an amino acid group, did not exhibit any hypolipidemic activity under a similar pharmacological protocol. Drug Dev. Res. 61:19–36, 2004. © 2004 Wiley‐Liss, Inc.     

1-Aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamide: an effective scaffold for the design of either CB1 or CB2 receptor ligands

New 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized as cannabinoid (CB) receptor ligands. Compound 11 (CB₁K_i = 2.3 nM, CB₁ SI = 163.6) showed CB₁ receptor affinity and selectivity superior to Rimonabant and AM251. Acute administration of 2 mg/kg 11 reduced sucrose, but not regular food, intake in rats. On the other hand, compound 23 (CB₂K_i = 0.51 nM, CB₂ SI = 30.0) showed significant affinity and selectivity for the CB₂ receptor. The results presented here show that the 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamide may serve as an effective scaffold for the design of either CB₁ or CB₂ receptor ligands.     

Boronic acid with high oxidative stability and utility in biological contexts

Despite their desirable attributes, boronic acids have had a minimal impact in biological contexts. A significant problem has been their oxidative instability. At physiological pH, phenylboronic acid and its boronate esters are oxidized by reactive oxygen species at rates comparable to those of thiols. After considering the mechanism and kinetics of the oxidation reaction, we reasoned that diminishing electron density on boron could enhance oxidative stability. We found that a boralactone, in which a carboxyl group serves as an intramolecular ligand for the boron, increases stability by 10⁴-fold. Computational analyses revealed that the resistance to oxidation arises from diminished stabilization of the p orbital of boron that develops in the rate-limiting transition state of the oxidation reaction. Like simple boronic acids and boronate esters, a boralactone binds covalently and reversibly to 1,2-diols such as those in saccharides. The kinetic stability of its complexes is, however, at least 20-fold greater. A boralactone also binds covalently to a serine side chain in a protein. These attributes confer unprecedented utility upon boralactones in the realms of chemical biology and medicinal chemistry.

The modern pharmacopeia is composed of only a handful of elements. Built on hydrocarbon scaffolds (1), nearly all drugs contain nitrogen and oxygen, and many contain fluorine and sulfur (2). A surprising omission from this list is the fifth element in the periodic table, boron (3, 4). Since bortezomib received regulatory approval in 2003, only four additional boron-containing drugs have demonstrated clinical utility (Fig. 1A). Each is a boronic acid or ester.Open in a separate windowFig. 1.(A) Food and Drug Administration–approved pharmaceuticals containing a boronic acid. (B) Putative mechanism for the oxidative deboronation of a boronic acid by hydrogen peroxide (30).Bortezomib is a boronic acid, and ixazomib citrate hydrolyzes to one in aqueous solution (5). Other boron-containing drugs feature cyclic esters. The cyclic ester formed spontaneously from 2-hydroxymethylphenylboronic acid (2-HMPBA) is known as “benzoxaborole” and has received much attention due to its enhanced affinity for saccharides at physiological pH (6–8). This scaffold is present in the antifungal drug tavaborole and the antidermatitis drug crisaborole (9). Vaborbactam, which contains an analogous six-membered ring, is an efficacious β-lactamase inhibitor (10). Neuropathy has been associated with the use of bortezomib but not other boronic acids, which have minimal toxicity (11).The boron atom in a boronic acid (or ester) is isoelectronic with the carbon atom of a carbocation. Both are sp² hybridized, have an empty p orbital, and adopt a trigonal planar geometry. In contrast to a carbocation, however, the weak Lewis acidity of a boronic acid allows for the reversible formation of covalent bonds. This attribute has enabled boronic acids to achieve extraordinary utility in synthetic organic chemistry and molecular recognition (12–22). Boronic acids are, however, susceptible to oxidative damage. That deficiency is readily controllable in a chemistry laboratory but not in a physiological environment.In a boronic acid, the empty p orbital of boron is prone to attack by nucleophilic species such as the oxygen atom of a reactive oxygen species (ROS). The subsequent migration of carbon from boron to that oxygen leads to a labile boric ester which undergoes rapid hydrolysis (Fig. 1B). This oxidative deboronation converts the boronic acid into an alcohol and boric acid (23, 24).We sought a means to increase the utility of boron in biological contexts by deterring the oxidation of boronic acids. The rate-limiting step in the oxidation of boronic acid is likely to be the migration of carbon from boron to oxygen: a 1,2-shift (Fig. 1B). In that step, the boron becomes more electron deficient. We reasoned that depriving the boron of electron density might slow the 1,2-shift. A subtle means to do so would be to replace the alkoxide of a boronate ester with a carboxylate group. We find that the ensuing mixed anhydrides between a boronic acid and carboxylic acid are remarkable in their chemical attributes and biological utility.     

Synthesis of new pyrazolo[3,4‐d]pyrimidine derivatives and evaluation of their anti‐inflammatory and anticancer activities

This study reports the synthesis of two series of new purine bioisosteres comprising a pyrazolo[3,4‐d]pyrimidine scaffold linked to piperazine moiety through different amide linkages. The newly synthesized compounds were evaluated for anticancer activity against four cell lines (MDA‐MB‐231, MCF‐7, SF‐268, B16F‐10) and cyclooxygenase (COX‐2) protein expression inhibition in lipopolysaccharide (LPS)‐activated rat monocytes. The results revealed that most of the synthesized compounds showed moderate‐to‐high cytotoxic activity against at least one cell line, with compound 10b being the most active against all used cell lines (IC₅₀ values 5.5–11 μg/ml) comparable to cisplatin. In addition, six of these compounds ( 7b, 10a–d, and 12c ) demonstrated inhibition of LPS‐induced COX‐2 protein expression at low concentration (25 μg/ml) as compared to the control non‐stimulated cells and showed a COX‐2 selectivity index range comparable to diclofenac sodium. The overall results indicate that many of these pyrazolopyrimidine derivatives possess in vitro anti‐inflammatory and anticancer activities at varying doses, and the most active compounds will be subjected to in vivo pharmacological evaluation.     

Derivatives of 4-(2-N,N-Di-n-propylaminoethyl)-5-hydroxyindole: Synthesis and Pharmacological Effects

5-Methoxy-l-methyl-4-(2-N,N-di-n-propylaminoethyl)indole (12) was synthesized from 5-hydroxyindole by a multistep synthesis. This target compound was designed as a bioisostere of p-dimethoxy catechol congeners of dopaminergic agonists derived from a variety of ring systems, in some of which p-dimethoxy-substituted systems are potent, active dopaminergic agonists. To complete the indole series, all possible combinations of N- and O-demethylated derivatives of 12 were prepared and were also evaluated pharmacologically. All members of this indole-derived series showed a low order of cardiovascular activity, which appeared to be independent of dopamine receptors. The lack of dopaminergic activity of 12 is cited as yet another example of the unpredictable effect of replacement of the catechol moiety of a dopaminergic agonist with a p-dimethoxy moiety.To whom correspondence should be addressed.     

药用有机硅化合物的研究进展

目的 综述元素硅在先导化合物优化中的应用及其特点,从而为新药设计提供理论依据。方法 对近年来国内外发表的文献进行归纳、总结。 结果与结论 对现有药物或候选药物进行碳/硅交换是一种寻求新化学实体的有效方法。     

Synthesis of 1-methyl-5-(pyrazol-3- and -5-yl- and 1, 2, 4-triazol-3- and 5-yl)-1, 2, 3, 6-tetrahydropyridine derivatives and their evaluation as muscarinic receptor ligands

A series of 1-methyl-5-(pyrazol-3- and -5-yl- and 1, 2, 4-triazol-3- and 5-yl)-1, 2, 3, 6-tetrahydropyridine derivatives structurally related to arecoline were synthesized and evaluated on M(1), M(2), and M(3) muscarinic receptors using [(3)H] pirenzepine and [(3)H] NMS as ligands. The binding affinity depended on the position and size of the substituents. The most interesting compounds were further evaluated in functional studies on isolated organs and in vivo for cholinergic side effects. Compounds 5 l and 6 i good M(1) and M(3) antagonistic properties in vitro and were devoid of cholinergic side effects in vivo.