Solo Goldstein

IAM retention and blood brain barrier penetration

A series of 1,3,5-triazines possessing bronchospasmolytic, antiinflammatory and central nervous system activities have been chromatographically characterized using commercially available immobilized artificial membrane (IAM) columns. The obtained capacity factors correlated well (r = 0.97) with the shake-flask octanol—buffer (log P) partition coefficient but less well (r = 0.72) with capacity factors obtained using RP-HPLC columns (log k′w). Moreover it was shown that the potentiation of oxotremorine-induced tremors, observed for this class of compounds correlated well with both log P and log k′IAM parameters. On the contrary such a correlation did not exist when using Δlog P (log Pinoctanol—water — log Pincyclohexane—water). Thus the determination of log k′IAM is a fast, reliable and efficient method for assessing lipophilic behaviour of 1,3,5-triazines in connection with CNS-related biological activities.

Synthesis and pharmacological evaluation of thieno[2,3-b]pyridine derivatives as novel c-Src inhibitors

Among the recently investigated targets for cancer therapy is the c-Src non-receptor tyrosine kinase. Indeed research around deregulated activity of this enzyme has proven its role in tumor progression, while the beneficial effects of c-Src inhibitors in several pathological models has also been demonstrated. We report here the preparation and pharmacological profile of a novel series of c-Src inhibitors that was elaborated around a 3-amino-thieno[2,3-b]pyridine discovered during an HTS campaign. c-Src enzyme inhibition and c-Src inhibition were investigated in a series of related compounds derived from the initial hit. Molecular modeling as well as X-ray studies on one active compound allowed us to hypothesize on ligand orientation and interactions within the ATP hydrophobic pocket. Design and synthesis of structural analogs then led to new ligands possessing quite efficient enzymatic and c-Src inhibition. The structure-activity elements disclosed in this study shed light on the role played by substituents on the thienopyridine ring as well as the impact of other aromatic moieties in the molecule when interacting with the enzyme.

Synthesis and pharmacological evaluation of new 1,2-dithiolane based antioxidants

Molecules containing a dithiolane moiety are widely investigated due to their antioxidant properties. The archetypal representative of this class of compounds is lipoic acid and indeed the lipoic acid-dihydrolipoic acid couple is part of the antioxidant defence system of the cell. In the course of a program aiming to find improved antioxidants effective in vivo, we designed, synthesised and pharmacologically investigated new lipoic acid analogs. The salient feature of these structures is the connection, via a thioamide or a thiocarbamate, of a 1,2-dithiolane moiety bearing a carbon chain and a N-alkyl-substituted morpholine ring. It was expected that the antioxidant and chelating properties of these functional groups combined with the basicity of the morpholine ring will impact on the antioxidant as well as on the partition and solubility characteristics of the compounds. Indeed in vitro and in vivo pharmacological investigation showed that these new molecules and especially those containing a thiocarbamate linker possess superior antioxidant properties compared with alpha-lipoic acid and to the amide or carbamate linker analogs. In particular, some of these compounds efficiently cross the blood brain barrier (BBB) thus providing efficient protection from lethality in a situation of induced oxidative stress. Moreover the absence of the 1,2-dithiolane moiety does not completely abolish antioxidant effects thus demonstrating that these compounds are distinct new chemical entities and not merely lipoic acid prodrugs. The chemical and pharmacological features of these new antioxidants are presented and discussed in the following paper.

Bioactive conformations of peptides and mimetics as milestones in drug design: Investigation of NK1 receptor antagonists

Nine potent and selective substance P receptor antagonists (NK1 -) were analyzed with respect to their conformational space, with the aim to suggest probable conformations adopted at the receptor site and superposition rules for each structure (pharmacophore mapping). Key atoms within the ligands as well as receptor site points were considered in order to identify acceptable solutions (DISCO program). The results obtained allowed the suggestion or probable peptidic pharmacophores based on the structure of 1 (FK888). This knowledge was used to search commercial databases. The number and diversity of known retrieved NK1 antagonists allowed a general evaluation of the proposed pharmacophores. Moreover, a search in our proprietary database detected a short peptide with modest affinity but high selectivity for the NK1 receptor. The combination of molecular modeling with database searches is useful in a strategy aiming to develop new NK1 antagonists starting from existing knowledge.

S 50131 and S 51434, two novel small molecule glucokinase activators, lack chronic efficacy despite potent acute antihyperglycaemic activity in diabetic mice.

Small molecule glucokinase activators (GKAs) have been associated with potent antidiabetic efficacy and hepatic steatosis in rodents. This study reports the discovery of S 50131 and S 51434, two novel GKAs with an original scaffold and an atypical pharmacological profile.

Preparation and affinity profile of novel nicotinic ligands

Novel nicotinic ligands, characterized by the presence of an amino substituted cyclopropane ring connected to a pyridine nucleus, are described. Pharmacological investigation revealed that these compounds exhibit highest affinity for the rat alpha4beta2 subtype of the nicotinic receptor with no affinity for the muscarinic receptor. No appreciable affinity for the muscular or for the ganglionic nicotinic receptor was observed at concentrations up to 10 microM. The increase in cortical ACh release as well as a positive effect on memory in a social recognition test in rat are exemplified.

Conformational analysis of pseudo-peptides: The case of FK888, a potent and selective substance P receptor antagonist

Molecular recognition is a central problem in medicinal sciences, and therefore a knowledge of the salient molecular features neccessary for efficient interaction with a receptor as well as their relative spatial arrangement is of crucial importance. Thus, an insight into probable biorelevant 3D structures by conformational analysis is equally fundamental. In the present study, we describe the conformational analysis of FK888, a potent and selective pseudo-peptide antagonist of the NK1 receptor of substance P, using an in-house developed method (CONFEX: CONFormational EXploration). Conformations could be subdivided into four families according to peptidic folding: the first two present an extended conformation which can be characterized as a hairpin-like structure, while the other two present a β-turn-like arrangement. These results were compared with experimental findings obtained by NMR spectroscopy.

Comparative conformational analysis of two endothelin-B antagonists

A comparative conformational analysis of two short pseudopeptides with ETB receptor affinity has been performed by molecular modelling and NMR techniques. This analysis aimed to get insight into probable biorelevant conformations and pharmacophoric patterns necessary for an efficient interaction with the receptor. Thus, it was shown that the two compounds can adopt γ-turn (or γ-turn-like) conformations, based on which the synthesis of particular, more rigid analogs might be proposed. The results obtained should prove valuable in a strategy aiming to design new endothelin antagonists following a peptide to non-peptide approach.