We have identified two chemical series of compounds acting as selective positive allosteric modulators (enhancers) of native and recombinant metabotropic glutamate 1 (mGlu1) receptors. These compounds did not directly activate mGlu1 receptors but markedly potentiated agonist-stimulated responses, increasing potency and maximum efficacy. Binding of these compounds increased the affinity of a radiolabeled glutamate-site agonist at its extracellular N-terminal binding site. Chimeric and mutated receptors were used to localize amino acids in the receptor transmembrane region critical for these enhancing properties. Finally, the compounds potentiated synaptically evoked mGlu1 receptor responses in rat brain slices. The discovery of selective positive allosteric modulators of mGlu1 receptors opens up the possibility to develop a similar class of compounds for other family 3 G protein-coupled receptors.

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We have synthesized several 4-aminoquinolines with shortened side chains that retain activity against chloroquine-resistant isolates of Plasmodium falciparum malaria (W. Hofheinz, C. Jaquet, and S. Jolidon, European patent 94116281.0, June 1995). We report here an assessment of the activities of four selected compounds containing ethyl, propyl, and isopropyl side chains. Reasonable in vitro activity (50% inhibitory concentration, < 100 nM) against chloroquine-resistant P. falciparum strains was consistently observed, and the compounds performed well in a variety of plasmodium berghei animal models. However, some potential drawbacks of these compounds became evident upon in-depth testing. In vitro analysis of more than 70 isolates of P. falciparum and studies with a mouse in vivo model suggested a degree of cross-resistance with chloroquine. In addition, pharmacokinetic analysis demonstrated the formation of N-dealkylated metabolites of these compounds. These metabolites are similarly active against chloroquine-susceptible strains but are much less active against chloroquine-resistant strains. Thus, the clinical dosing required for these compounds would probably be greater for chloroquine-resistant strains than for chloroquine-susceptible strains. The clinical potential of these compounds is discussed within the context of chloroquine's low therapeutic ratio and toxicity.

The GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.

New orally active non-terpenoic inhibitors of human 2,3-oxidosqualene cyclase (hOSC) are reported. The starting point for the optimization process was a set of compounds derived from a fungicide project, which in addition to showing high affinity for OSC from Candida albicans showed also high affinity for human OSC. Common structural elements of these inhibitors are an amine residue and an electrophilic carbonyl C atom embedded in a benzophenone system, which are at a distance of about 10.7 A. Considering that the keto moiety is in a potentially labile position, modifications of the substitution pattern at the benzophenone as well as annelated heteroaryl systems were explored. Our approach combined testing of the compounds first for increased binding affinity and for increased stability in vitro. Most promising compounds were then evaluated for their efficacy in lowering plasma total cholesterol (TC) and plasma low-density lipoprotein cholesterol (LDL-C) in hyperlipidemic hamsters. In this respect, the most promising compounds are the benzophenone derivative 1.fumarate and the benzo[d]isothiazol 24.fumarate, which lowered TC by 40% and 33%, respectively.

Investigations on Aromatic Amino‐Claisen Rearrangements The thermal and acid catalysed rearrangement of p‐substituted N‐(1′,1′‐dimethylallyl)anilines (p‐substituent=H (5), CH3 (6), iso‐C3H7 (7), Cl (8), OCH3 (9), CN (10)), of N‐(1′,1′‐dimethylallyl)‐2,6‐dimethylaniline (11), of o‐substituted N‐(1′‐methylallyl)anilines (o‐substituent=H (12), CH3 (13), t‐C4H9 (14), of (E)‐ and (Z)‐N‐(2′‐butenyl)aniline ((E)‐ and (Z)‐16), of N‐(3′‐methyl‐2′‐butenylaniline (17) and of N‐allyl‐(1) and N‐allyl‐N‐methylaniline (15) was investigated (cf. Scheme 3). The thermal transformations were normally conducted in 3‐methyl‐2‐butanol (MBO), the acid catalysed rearrangements in 2N‐0,1N sulfuric acid. ‐ Thermal rearrangements. The N‐(1′,1′‐dimethylallyl)anilines rearrange in MBO at 200‐260° with the exception of the p‐cyano compound 10 in a clean reaction to give the corresponding 2‐(3′‐methyl‐2′‐butenyl)anilines 22–26 (Table 2 and 3). The amount of splitting into the anilines is <4% (10 gives ≃ 40% splitting). The secondary kinetic deuterium isotope effect (SKIDI) of the rearrangement of 5 and its 2′,3′,3′‐d3‐isomer 5 amounts to 0.89±0.09 at 260° (Table 4). This indicates that the partial formation of the new s̀‐bond C(2), C(3′) occurs already in the transition state, as is known from other established [3,3]‐sigmatropic rearrangements. The rearrangement of the N‐(1′‐methylallyl)anilines 12–14 in MBO takes place at 290–310° to give (E)/(Z)‐mixtures of the corresponding 2‐(2′‐Butenyl)anilines ((E)‐ and (Z)‐30,‐31, and ‐32) besides the parent anilines (5–23%). Since a dependence is observed between the (E)/(Z)‐ratio and the bulkiness of the o‐substituent (H: (E)‐30/(Z)‐30=4,9; t‐C4H9: (E)‐32/(Z)‐32=35.5; cf. Table 6), it can be concluded, that the thermal amino‐Claisen rearrangement occurs preferentially via a chair‐like transition state (Scheme 22). Methyl substitution at C(3′) in the allyl chain hinders the thermal amino‐Claisen‐rearrangement almost completely, since heating of (E)‐and (Z)‐16, in MBO at 335° leads to the formation of the expected 2‐(1′‐methyl‐allyl) aniline (33) to an extent of only 12 and 5%, respectively (Scheme 9). The main reaction (≃60%) represents the splitting into aniline. This is the only observable reaction in the case of 17. The inversion of the allyl chain in 16 ‐ (E)‐ and (Z)‐30 cannot be detected ‐ indicated that 33 is also formed in a [3, 3]‐sigmatropic process. This is also true for the thermal transformation of N‐allyl‐(1) and N‐allyl‐N‐methylaniline (15) into 2 and 34, respectively, since the thermal rearrangement of 2′, 3′, 3′‐d3‐1 yields 1′, 1′, 2′‐d3‐2 exclusively (Table 8). These reaction are accompanied to an appreciable extent by homolysis of the N, C (1′) bond: compound 1 yields up to 40% of aniline and 15 even 60% of N‐methylaniline ((Scheme 10 and 11). The activation parameters were determined for the thermal rearrangements of 1, 5, 12 and 15 in MBO (Table 22). All rearrangements show little solvent dependence (Table 5, 7 and 9). The observed ΔH≠ values are in the range of 34‐40 kcal/mol and ...

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