Abstract:Retrometabolic approaches represent systematic drug design methodologies that thoroughly integrate structure—activity and structure—metabolism relationships and are aimed to design safe compounds with an improved therapeutic index. They incorporate two major concepts aimed to design soft drugs and chemical delivery systems, respectively. Soft drugs are new, active therapeutic agents that undergo predictable metabolism to inactive metabolites after exerting their desired therapeutic effect. Chemical delivery sy… Show more
“…Soft anticholinergic agents designed (Figure ) using the soft drug approach of the general retrometabolism-based drug design and targeting concept − can provide viable solutions for the problems faced during the development of local anticholinergics. Soft drugs are biologically active molecules, often isosteric/isoelectronic analogues of a lead compound, specifically designed to allow predictable metabolism into inactive metabolites after exerting the desired therapeutic effect.…”
Section: Introductionmentioning
confidence: 99%
“…In most cases, soft drugs are expected to produce pharmacological activity locally but be rapidly deactivated by metabolic (preferably hydrolytic) processes as they distribute away from their site of action to prevent any kind of undesired pharmacological activity or toxicity. Because a locally active soft anticholinergic, which has high local but practically no systemic activity, can provide a viable solution to many of the problems hindering the development of anticholinergic drugs, different series of soft anticholinergics based on methylatropine ( 1 ), N -methylscopolamine ( 2 ), glycopyrrolate ( 4 ), propantheline ( 5 ), or other lead structures were designed and tested during the last two-and-a-half decades (see refs and for detailed reviews). 1 The general design concept of soft anticholinergics agents.…”
A comprehensive quantitative structure-activity relationship (QSAR) study is presented for quaternary soft anticholinergics including two distinctly different classes designed on the basis of the soft analogue and the inactive metabolite approaches. Because of the clear biphasic (bilinear) nature of the activity data when all structures (n = 76) were considered as a function of molecular size (volume), a nonlinear model had to be used, and a linearized biexponential (LinBiExp) model proved very adequate. LinBiExp can fit activity data that show a maximum (or a minimum) around a given parameter value but tend to show linearity away from this turning point. Contrary to Hansch-type parabolic models, LinBiExp represents a natural extension of linear models, and a direct correspondence between its parameters and those obtained earlier by linear regression on compound subsets covering more limited parameter ranges could be easily established. Stereospecificity was confirmed as important, and the presence of an acid moiety was found to essentially eliminate activity. The consideration of bilinear behavior, which most likely results from size limitations at the binding site, can also explain the embarrassingly low activity found for a relatively large compound predicted as highly active by Lien, Ariëns, and co-workers based on their QSAR study.
“…Soft anticholinergic agents designed (Figure ) using the soft drug approach of the general retrometabolism-based drug design and targeting concept − can provide viable solutions for the problems faced during the development of local anticholinergics. Soft drugs are biologically active molecules, often isosteric/isoelectronic analogues of a lead compound, specifically designed to allow predictable metabolism into inactive metabolites after exerting the desired therapeutic effect.…”
Section: Introductionmentioning
confidence: 99%
“…In most cases, soft drugs are expected to produce pharmacological activity locally but be rapidly deactivated by metabolic (preferably hydrolytic) processes as they distribute away from their site of action to prevent any kind of undesired pharmacological activity or toxicity. Because a locally active soft anticholinergic, which has high local but practically no systemic activity, can provide a viable solution to many of the problems hindering the development of anticholinergic drugs, different series of soft anticholinergics based on methylatropine ( 1 ), N -methylscopolamine ( 2 ), glycopyrrolate ( 4 ), propantheline ( 5 ), or other lead structures were designed and tested during the last two-and-a-half decades (see refs and for detailed reviews). 1 The general design concept of soft anticholinergics agents.…”
A comprehensive quantitative structure-activity relationship (QSAR) study is presented for quaternary soft anticholinergics including two distinctly different classes designed on the basis of the soft analogue and the inactive metabolite approaches. Because of the clear biphasic (bilinear) nature of the activity data when all structures (n = 76) were considered as a function of molecular size (volume), a nonlinear model had to be used, and a linearized biexponential (LinBiExp) model proved very adequate. LinBiExp can fit activity data that show a maximum (or a minimum) around a given parameter value but tend to show linearity away from this turning point. Contrary to Hansch-type parabolic models, LinBiExp represents a natural extension of linear models, and a direct correspondence between its parameters and those obtained earlier by linear regression on compound subsets covering more limited parameter ranges could be easily established. Stereospecificity was confirmed as important, and the presence of an acid moiety was found to essentially eliminate activity. The consideration of bilinear behavior, which most likely results from size limitations at the binding site, can also explain the embarrassingly low activity found for a relatively large compound predicted as highly active by Lien, Ariëns, and co-workers based on their QSAR study.
“…Slow and easily saturable oxidative pathways are avoided in favour of hydrolytic deactivation pathways. The main advantages of this approach in drug design are as follows: first, improvement of the therapeutic index by eliminating the formation of biologically active metabolites and toxic intermediates; second, elimination of many metabolic drug interactions by avoiding saturable enzymatic processes; and third, simplification of the drug pharmacokinetics (Bodor & Buchwald 2003). This leads to the formation of drugs with an enhanced margin of safety (i.e.…”
Quaternary ammonium surfactants, such as benzalkonium chloride and cetylpyridinium chloride, are commonly used as antibacterial agents for disinfectants and for general environmental sanitation, as well as in surfactants, penetration enhancers and preservatives in pharmaceutical and cosmetic formulations. However, these agents are known to cause various side-effects and toxic reactions that are believed to be associated with their chemical stability. Soft analogues of the long-chain quaternary ammonium compounds were synthesized according to the soft drug approach and their physicochemical properties investigated, such as their hydrolytic rate constant, surface activity and lipophilicity. Structure-activity studies showed that the antimicrobial activity of the compounds was strongly influenced by their lipophilicity and chemical stability, the activity increasing with increasing lipophilicity and stability. However, in soft drug design structure-activity relationships are combined with structure-inactivation relationships during the lead optimization. The safety index (SI) of compounds was defined as the hydrolytic rate constant divided by the minimum inhibitory concentration. The SI of the soft antibacterial agents was found to increase with increasing lipophilicity but optimum SI was obtained when their hydrolytic t1/2, at pH 6 and 60 degrees C, was about 11 h. Optimization of the soft antibacterial agents through SI optimization resulted in potent but chemically unstable quaternary ammonium antibacterial agents.
“…Previously, in work related to the brain-targeted delivery of neuropeptides, we have shown that in various arginine (Arg, R)-, histidine (His, H)-or lysine (Lys, K)-containing peptides, the original basic amino acid could be replaced by novel redox amino acids (Nys ↔ Nys + ), which contain a 1,4dihydrotrigonelline ↔ quaternary trigonelline side-chain, without activity-loss due to the sufficiently close steric and electronic analogy between the quaternary form of the redox (Nys + ) and the original side-chains (in their protonated form, Arg + , Lys + ) ( Figure 1) (Chen et al 1998;Bodor & Buchwald 2003b). This analogy is further illustrated in Figure 2 by comparing kyotorphine (Tyr-Arg, YR), an endogenous neuropeptide that exhibits analgesic action through the release of endogenous enkephalin and has analgesic activity about four times larger than Met-enkephalin (Takagi et al 1979), and its redox analogue in its permanently charged form, Tyr-Nys + .…”
mentioning
confidence: 99%
“…This analogy is further illustrated in Figure 2 by comparing kyotorphine (Tyr-Arg, YR), an endogenous neuropeptide that exhibits analgesic action through the release of endogenous enkephalin and has analgesic activity about four times larger than Met-enkephalin (Takagi et al 1979), and its redox analogue in its permanently charged form, Tyr-Nys + . Incorporation of the Nys moiety into the structure of neuropeptides resulted in brain-targeted redox analogue (BTRA) peptides that made possible the non-invasive brain delivery of these important biomolecules in pharmacologically significant amounts (Chen et al 1998;Bodor & Buchwald 2003b), and the peptide with the Nys + amino acid, metabolically formed from the originally administered Nys form, produced CNS activity due to the close analogy of its quaternary nicotinamide-containing side-chain with kyotorphine's Arg sidechain, which is always ionized under physiological conditions. Therefore, it seemed reasonable to investigate whether the replacement of the guanidinium headgroups of arginines by such permanently charged Nys + redox amino acids still maintains the cell-penetrating activity of the molecular transporter peptides.…”
Various cell-penetrating peptides have been discovered recently that can translocate across plasma membranes and can even carry large cargo molecules into the cells. Because under physiological conditions most of these peptides carry considerable positive charges due to the presence of basic amino acids such as arginine, we decided to investigate whether molecular transporters composed of permanently charged side-chains also possess such cell penetrating ability. Arginine-rich oligomers that have a backbone with increased flexibility due to incorporation of non-alpha-amino acids (epsilon-aminocaproic acid) have been found to be effective molecular transporters. Here, we report the preparation of analogue structures by replacing the arginine residues with the quaternary form of a novel redox amino acid (Nys(+)) that contain a trigonelline moiety; it has already been shown possible to replace the original basic amino acid side-chain of neuropeptides without significant activity-loss due to the sufficiently close steric and electronic analogy between the new Nys(+) and the original side-chains (in their protonated form, e.g., Arg(+), Lys(+)). A nonamer analogue showed transporter activity resulting in increased cellular uptake in human carcinoma (HeLa) cells.
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