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Serotonin antagonist reuptake inhibitor (SARI) drugs that block both 5-HT(2) receptors and the serotonin transporters have been developed. The human 5-HT(2A/2C) receptor has been implicated in several neurological conditions, and potent selective 5-HT(2A/2C) ligands may have therapeutic potential for treatment of CNS diseases such as depression. An imidazole moiety usually provides good pharmacokinetic properties as a drug substance, and thus considerable efforts have been devoted to develop imidazole derivatives into drug candidates. The imidazole series of compounds was evaluated against 5-HT(2A/2C) and serotonin reuptake inhibition. A few of the compounds in the series showed promising IC(50) values and antidepressant-like effect in in vivo forced swimming test (FST). On the basis of these results, further lead optimization studies resulted in identifying promising compounds potentially for therapeutic use.

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Since the CB1 cannabinoid receptor antagonist 1 (SR141716, rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. In the present study, biarylpyrazole analogues based on a pyrazole core coupled with 1,3,4-oxadiazole were synthesized and tested for CB1 receptor binding affinity. Thorough SAR studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole ring led to several novel CB1 antagonists with IC(50) approximately 1 nM for the CB1 receptor binding. Among these analogues, we identified 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1,3,4-oxadiazole 43c as a promising precandidate for the development as an antiobesity agent.

The natural (+)-lasonolide A (1), an anti-tumor agent, has been synthesized via thermodynamic benzylidene formation at the C 22 quaternary chiral center, use of a disulfone equivalent for elongation of the C 15 -C 17 three-carbon chain as well as introduction of the two trans olefins at C 15 and C 17 , iodocyclization for the upper THP, Michael addition for the bottom THP, and intramolecular Horner-Emmons olefination for the 20-membered macrolactone.In 1994, McConnel et al. identified lasonolide A from the shallow water Caribbean marine sponge, Forcepia sp., during the search for new anti-tumor agents from marine resources. 1 Lasonolide A exhibits anti-neoplastic activity by antagonizing the in vitro proliferation of A-549 human lung carcinoma cells as well as cell adhesion in a cell assay for the detection of signal-transduction agents. 2 Its relative stereochemistry was originally proposed incorrectly by extensive spectroscopic studies, and later revised as shown in 1, with the stereochemistry of the C 28 hydroxyl group and the absolute configuration, based on synthetic studies. 3,4 Lasonolide A is a novel 20-membered macrolactone, which comprises two cis-2,6-disubstituted tetrahydorpyrans, nine chiral centers including a quaternary center, and seven olefinic double bonds composed of one terminal, two cis and four trans olefins. The intriguing structural and biological features of the natural product attracted us to its total synthesis. In this paper, we present an efficient asymmetric total synthesis of the natural product (+)-lasonolide A (1).Following the retrosynthetic analysis of 1, introduction of the double bonds at C 2 and C 25 was planned by an intramolecular Horner-Emmons olefination and a Wittig reaction, respectively (Scheme 1). The appositely functionalized intermediate 2 could be prepared by the JuliaKocieński sulfone-coupling protocol 5 of sulfone 3 and aldehyde 4. Formation of the two tetrahydropyranyl rings was envisaged as iodocyclization of d-hydroxyalkene 5 for 3 and by intramolecular Michael addition of 7 for 4. While the quaternary center in 5 was proposed to be installed by thermodynamic differentiation of the two alkoxymethyl groups of 6, the homoallylic alkoxy group of 7 was conceived to be derived from an asymmetric allylation of the known alkene 8.The synthesis commenced with Swern oxidation 6 of the known alcohol 9 7 followed by the asymmetric allylation with allylboronate 10r 8 to afford the homoallylic alcohol 6 in 86% yield and 78% ee (Scheme 2). It was necessary to differentiate between the two alkoxymethyl groups of 6 in the next stage. It was hoped that thermodynamic formation of benzylidene from 6 would favor 11 rather than 12, due to the hydrogen-bonding between the axial primary hydroxyl group and the two ring oxygens. To determine the optimal procedure benzaldehyde was reacted with 6 Scheme 1 Retrosynthetic analysis O O HO O O O OH O HO 35 28 25 22 21 17 15 14 2 4 O O O OTBS TBSO TBSO OTBS (EtO) 2 OP O 2 O OH TBSO TBSO 3 + O OHC OTBS 4 OH O O Ph 5 O O OH 6 O OTIPS 7 EtOOC O...

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Pyrimidine usually has good pharmacokinetic properties as a drug substance and considerable efforts have been devoted to develop pyrimidine derivatives into drug candidates. Arylpiperazine-containing pyrimidine 4-carboxamide derivatives were synthesized and evaluated for binding to serotonin receptors and transporter. Pyrimidine derivatives showed good antidepressant activity in FST (forced swimming test) animal model and also displayed no appreciable inhibitory activity against hERG channel blocking assay. Herein SAR studies of pyrimidine derivatives targeting serotonin receptors and transporter will be disclosed.

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