Although most epilepsies are adequately treated by conventional antiepileptic therapy, there remains an unfulfilled need for safer and more effective anticonvulsant agents. Starting from milacemide, a weak anticonvulsant, and trying to elucidate its mechanism of action, we discovered a structurally novel class of potent and preclinically safe anticonvulsants. Here we report the structure-activity relationship (SAR) study within this series of compounds. Different parts of the structural lead 2-[[4-(3-chlorobenzoxy)benzyl]amino]acetamide (6) were thus varied (Figure 1), and many potent anticonvulsants were found. As an outcome of this study, 57 ((S)-2-[[4-(3-fluorobenzoxy)benzyl]amino]propanamide methanesulfonate, PNU-151774E) emerged as a promising candidate for further development for its potent anticonvulsant activity and outstanding therapeutic indexes (TIs) in different animal tests.

A possible bioisosterism between the benzamido and the phenylimidazolidin-2-one moieties has been suggested on the basis of the similarity between the molecular electrostatic potential (MEP) of metoclopramide, a D2 receptor antagonist with weak 5-HT3 receptor antagonist properties, and zetidoline, a D2 receptor antagonist. Starting from this premise, a series of phenylimidazolidin-2-one derivatives bearing a basic azabicycloalkyl or an imidazolylalkyl moiety were synthesized and evaluated for 5-HT3 receptor radioligand binding affinity ([3H]-GR 43,694). In vitro 5-HT3 receptor antagonist activity was tested in the guinea pig ileum assay (GPI). A number of high-affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the Bezold--Jarisch reflex in the anesthetized rat. In general, the imidazolylalkyl derivatives were found to be more active than azabicycloalkyls. 1-(3,5-Dichlorophenyl)-3-[(5-methyl-1H-imidazol-4-yl)methyl]imidazoli din-2-one (58), in particular, displayed very high affinity for the 5-HT3 receptor (Ki of 0.038 nM) with a Kb of 5.62 nM in the GPI assay, being more potent than the reference compounds (ondansetron, tropisetron, granisetron, and BRL 46,470) tested. 58 showed an ID50 comparable to that of ondansetron (2.2 micrograms/kg i.v.) in the Bezold--Jarisch reflex. A molecular modeling study based on this structurally novel series of compounds allowed the refinement of previously reported 5-HT3 receptor antagonist pharmacophore models.

The multikilogram production of the proline derivative 1, a key intermediate of a HIV protease inhibitor, required the design of a synthetic route able to be safely, effectively, and easily scaled up. Synthesis of the proline skeleton began with construction of racemic glycine derivative 4, via an ester enolate Claisen rearrangement of Boc-glycine 3-methyl-but-2-enyl ester (3) in the absence of a Lewis acid. After a classical resolution of 4 with (S)phenylglycinol, (S)-4 was transformed into bromo-lactone 6b with NBS. The bromo-lactone was transformed to proline alcohol 8 via a base-promoted rearrangement involving lactone solvolysis. An NMR study suggested that a bicyclic lactone was initially formed, which subsequently opened by the methanol solvent to form 8. The requisite ketone for fluorination was prepared via oxidation of the enantiomerically pure 8, using NaClO and catalytic TEMPO. gem-Difluoro proline 1 was then prepared from the ketone via fluorination with Deoxo-Fluor. During this study it was discovered that SiO 2 promoted fluorination by Deoxo-Fluor. This study allowed the production of 7.5 kg of 1 after 10 steps, in 4.5% molar yield and high purity (94-99% HPLC assay).

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