Introduced to the Market in the Last Decade (2001−2011) Jiang Wang,† María Sańchez-Rosello,́‡,§ Jose ́ Luis Aceña, Carlos del Pozo,‡ Alexander E. Sorochinsky, Santos Fustero,*,‡,§ Vadim A. Soloshonok,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry, Faculty of Pharmacy, University of Valencia, Av. Vicente Andreś Estelleś, 46100 Burjassot, Valencia, Spain Laboratorio de Molećulas Orgańicas, Centro de Investigacioń Príncipe Felipe, C/ Eduardo Primo Yuf́era 3, 46012 Valencia, Spain Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastian, Spain IKERBASQUE, Basque Foundation for Science, Alameda Urquijo, 36-5 Plaza Bizkaia, 48011 Bilbao, Spain Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska Street 1, 02660 Kyiv-94, Ukraine

Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011).

Years of cumulative research can result in the development of a clinically useful drug, providing either a cure for a particular disease or symptomatic relief from a physiological disorder. A lead compound with a desired pharmacological activity may have associated with it undesirable side effects, characteristics that limit its bioavailability, or structural features which adversely influence its metabolism and excretion from the body. Bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents. The concept of bioisosterism is often considered to be qualitative and intuitive.1 The prevalence of the use of bioisosteric replacements in drug design need not be emphasized. This topic has been reviewed in previous years.2-5 The objective of this review is to provide an overview of bioisosteres that incorporates sufficient detail to enable the reader to understand the concepts being delineated. While a few popular examples of the successful use of bioisosteres have been included, the George Patani graduated with a B.Pharm. in 1992 from the College of Pharmaceutical Sciences, Mangalore University at Manipal, India. In 1996, he received his M.S. in Pharmaceutical Science at Rutgers University under the direction of Professor Edmond J. LaVoie. He is presently pursuing graduate studies in pharmaceutics. His current research interests are focused on drug design and controlled drug delivery.

https://www.mch.estranky.sk/file/228/1996chemrev96-3147-76_bioisosterism.pdf

Bioisosterism: A Rational Approach in Drug Design.

In recent years, there has been an ever-increasing need for rapid reactions that meet the three main criteria of an ideal synthesis: efficiency, versatility, and selectivity. Such reactions would allow medicinal chemistry to keep pace with the multitude of information derived from modern biological screening techniques. The present review describes one of these reactions, the 1,3-dipolar cycloaddition ("click-reaction") between azides and alkynes catalyzed by copper (I) salts. The simplicity of this reaction and the ease of purification of the resulting products have opened new opportunities in generating vast arrays of compounds with biological potential. The present review will outline the accomplishments of this strategy achieved so far and outline some of medicinal chemistry applications in which click-chemistry might be relevant in the future.

Click chemistry reactions in medicinal chemistry: applications of the 1,3-dipolar cycloaddition between azides and alkynes.

Pharmacokinetics of selective serotonin reuptake inhibitors.

Do Novel Antipsychotics Have Similar Pharmacological Characteristics? A Review of the Evidence

The enantiomers of citalopram and N-demethylcitalopram have been investigated. Based on the inhibition of 5-HT uptake in vitro and the potentiation of 1-5-HTP in vivo the pharmacological activity resides in the (+)-enantiomers (the eutomers*) with the 1-(S) absolute configuration. In the 5-HT uptake test eudismic ratios of 167 and 6.6 are obtained for the enantiomers of citalopram and N-demethylcitalopram, respectively. The pharmacological profile of the eutomers of citalopram and N-demethylcitalopram very much resembles the profile of the respective racemates.

The pharmacological effect of citalopram residues in the (S)-(+)-enantiomer.

Rationale
Citalopram is a racemate consisting of a 1:1 mixture of the R(−)- and S(+)-enantiomers. Non-clinical studies show that the serotonin reuptake inhibitory activity of citalopram is attributable to the S-enantiomer, escitalopram. A series of recent non-clinical and clinical studies comparing escitalopram and citalopram to placebo found that equivalent doses of these two drugs, i.e. containing the same amount of the S-enantiomer, showed better effect for escitalopram. These results suggested that the R-citalopram in citalopram inhibits the effect of the S-enantiomer.

Escitalopram versus citalopram: the surprising role of the R -enantiomer

A series of 3-phenyl-1-indanamines was synthesized and tested for potential antidepressant activity and for inhibition of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) uptake. Trans isomers were generally potent inhibitors of DA, NE, and 5-HT uptake, while cis isomers preferentially inhibited the uptake of 5-HT. The affinity for the DA-uptake site was very dependent on the aromatic substitution pattern where highest potency was found for 3',4'-dichloro substituted compounds (45). This substitution pattern also resulted in high affinity for the NE-and 5-HT-uptake sites, but potent 5-HT-uptake inhibiting activity could also be obtained with other substitution patterns. Only small amines could be accommodated at the 5-HT-uptake site while larger amines such as piperazine could be accommodated both at the DA-and NE-uptake sites. The observed structure-activity relationships were explained from the results of superimpositions of a trans (45) and cis (72) isomer with 5-HT and DA, respectively, in relation to a proposed three-point binding of the uptake inhibitors at the uptake sites. Finally, comparison of the structures of the 3-phenyl-1-indanamines with other newer bicyclic catecholamine- and/or serotonin-uptake inhibitors revealed common structural elements important for potent DA-, NE-, and/or 5-HT-uptake inhibition.

3-Phenyl-1-indanamines. Potential antidepressant activity and potent inhibition of dopamine, norepinephrine, and serotonin uptake.

The effects of a range of dopamine (DA) agonists on stereotyped behaviour in rats were analysed and compared both with the affinity of the compounds for D1 and D2 receptor binding sites in vitro and their ability to stimulate the adenylate cyclase activity in rat striatal homogenates. Full and partial agonists at the D1 receptor coupled toadenylate cyclase do not induce stereotypies when given alone, whereas full D2 agonists (e.g. quinpirole) induce hyperactivity but not oral stereotypies. Partial D2 agonists (e.g. (—)-3-PPP) only induce sedation. Mixed D1/D2 agonists (e.g. apomorphine) induce both hyperactivity and oral stereotypies. Maximum stereotypies were induced by combination of SK & F 38393 and a series of D2 agonists, including full agonists and the partial D2 agonist B-HT 920, whereas partial agonists with low intrinsic activity (e.g. (-)-3-PPP, EMD 23448) did not induce stereotypies when given together with SK & F 38393. However, these partial agonists reduced the maximum effect of apomorphine, whereas the full agonists (e.g. quinpirole, (—)-NPA) and B-HT 920 had no apomorphine antagonistic activity. The mixed D1/D2 agonists apomorphine and N,N-dipropyl-5,6-ADTN were only weakly influenced by SK & F 38393, or not at all. D1 agonists with central effects, including SK & F 38393, SK & F 81297 (with relatively high efficacies), and the partial agonist SK & F 75670 with low efficacy, changed the hyperactivity induced by quinpirole into maximum oral stereotypy, whereas the peripheral D1 agonist fenoldopam had no such effect. Inhibition of DA and NA synthesis with α-methyl-p-tyrosine depleted striatal DA levels by 72 per cent and antagonized the hyperactivity induced by the D2 agonists quinpirole and (—)-NPA, but not that of apomorphine. Combination of SK & F 38393 and quinpirole induced maximum stereotypy in DA-depleted animals. These results suggest that D1 receptor tonus is a necessary prerequisite for the expression of a DA agonist's effect. The hyperactivity induced by full D2 agonists appears to be mediated by D1 tonus provided by endogenous DA activity, but stronger D1 stimulation is necessary to induce oral stereotypy. A high degree of D1 receptor activation increases the ability of partial D2 agonists to induce hyperactivity or oral stereotypies since treatment with both SK & F 38393 and B-HT 920 had marked effects while B-HT 920 was ineffective. The behavioural stimulation induced by a particular DA agonist thus depends on relative D1/D2 receptor affinity and also on the intrinsic activity at D2 receptors, while intrinsic activity at D1 receptors appears to be less important. The relative importance of D1 and D2 receptors for expression of different stereotypy patterns is useful for in vivo evaluation of the selectivity ratios of DA agonists.

Relative dopamine D1 and D2 receptor affinity and efficacy determine whether dopamine agonists induce hyperactivity or oral stereotypy in rats.

A series of arecoline bioisosteres, where the ester group is replaced by a 1,2,3-triazole-4-yl or a tetrazole-5-yl group, was synthesized and evaluated in vitro for affinity and efficacy at muscarinic receptors and in vivo for cholinergic side effects. The corresponding piperidine derivatives were also studied. In the 1,2,3,6-tetrahydropyridyl-1,2,3-triazole series, only derivatives with 2-substituents in the 1,2,3-triazole ring exert muscarinic agonist activity. The same trend is seen in the corresponding tetrazole series, where only 2-substituted derivatives display muscarinic agonist activity. The methyl derivatives in both series are full agonists, whereas the derivatives with longer side chains are partial agonists. Introduction of methyl substituents in the 1,2,3,6-tetrahydropyridine ring generally lowers affinity considerably except for the 3-substituted derivatives, where some activity is retained. In both the 1,2,3-triazole and tetrazole series, derivatives without substituents at the basic nitrogen in the 1,2,3,6-tetrahydropyridine ring are unselective full agonists, whereas the methyl-substituted derivatives generally are more M1 selective compared to M2. Larger substituents than methyl abolish activity. The 4-(3-piperidyl)-1,2,3-triazole and 5-(3-piperidyl)-2H-tetrazole derivatives are generally less active than the corresponding 1,2,3,6-tetrahydropyridine derivatives, and only the 2-allyl- and 2-propargyl-1,2,3-triazole derivatives display activities comparable to the most active compounds in the 1,2,3,6-tetrahydropyridine series. The propargyl derivative is an unselective full agonist, and resolution did not reveal any stereoselectivity The allyl derivative is a partial agonist with some selectivity for the M1 receptor, and testing of the enantiomers showed that the (+)-enantiomer is an unselective partial agonist, whereas the (-)-enantiomer is a partial agonist with preference for the M1 receptor. Generally, the structure-activity relationships of the 1,2,3-triazole and tetrazole series are very similar, and two compounds, 2-ethyl-4-(1-methyl-1,2,3,6-tetrahydro-5-pyridyl)-1,2,3-triazole and 2-ethyl-5-(1-methyl-1,2,3,6-tetrahydro-5-pyridyl)-2H-tetrazole, are M1 agonists/M2 antagonists. Muscarinic compounds with this profile are of particular interest as drugs for the treatment of Alzheimer's disease.

Bioisosteres of arecoline: 1,2,3,6-tetrahydro-5-pyridyl-substituted and 3-piperidyl-substituted derivatives of tetrazoles and 1,2,3-triazoles. Synthesis and muscarinic activity.

Klaus Peter Bogeso

Papers

The pharmacological effect of citalopram residues in the (S)-(+)-enantiomer.

Escitalopram versus citalopram: the surprising role of the R -enantiomer

3-Phenyl-1-indanamines. Potential antidepressant activity and potent inhibition of dopamine, norepinephrine, and serotonin uptake.

Relative dopamine D1 and D2 receptor affinity and efficacy determine whether dopamine agonists induce hyperactivity or oral stereotypy in rats.

Bioisosteres of arecoline: 1,2,3,6-tetrahydro-5-pyridyl-substituted and 3-piperidyl-substituted derivatives of tetrazoles and 1,2,3-triazoles. Synthesis and muscarinic activity.