The current status and future perspectives of studies of cannabinoid receptor 1 antagonists as anti-obesity agents.

Since the discovery of rimonabant (Acomplia: 1), a large effort has been directed at the discovery of new, potent and selective CB(1)R antagonists that serve as anti obesity drugs. As a result, a number of compounds reached various stages of clinical trials by late 2008. However, the announcement by Sanofi-Aventis that they were discontinuing all ongoing trials with rimonabant, as a result of the finding that risks associated with depression and anxiety outweighed its benefits, had a major impact on this area. A wave of terminations of programs targeting the development of CB(1)R blockers for treatment of obesity ensued. However, abandoning this CB(1)R therapeutic target for anti-obesity drug development seems to be premature, since there are a number of potential approaches have been uncovered to circumvent the problems of the current agents. In this review, we summarize advances that have been made and the status of studies of a diverse array of CB(1)R antagonists that have been identified mainly based on modifications of the first-in-class CB(1)R antagonist, rimonabant. Various approaches have been employed to design these analogs, such as bioisosteric replacement, introduction of conformational constraints, scaffold hopping and ligand-based molecular modeling. In addition, current approaches that have been uncovered to avoid psychiatric side effects of CB(1)R antagonists are summarized. Finally, the design of non-brain penetrating and peripherally acting CB(1)R antagonists, allosteric modulators of CB(1)R, and neutral antagonists for CB(1)R is also discussed in this review.

Identification of 3-acetyl-2-aminoquinolin-4-one as a novel, nonpeptidic scaffold for specific calpain inhibitory activity.

A series of 3-acetyl-2-aminoquinolin-4-one derivatives selected from the Korean Chemical Bank were screened for calpain inhibitory activity by using a high-throughput fluorimetric calpain assay. We identified a potent and selective mu-calpain inhibitor, compound 17, whose specificity and efficacy for mu-calpain inhibition was better than MDL28170. Docking studies revealed that the efficacy of its inhibitory effect on calpain depended on the size and charge properties of the substitutions on the phenylamino ring.

PTP-1B inhibitors: cyclopenta[d][1,2]-oxazine derivatives.

A series of novel cyclopenta[d][1,2]-oxazine derivatives was prepared and evaluated for their inhibitory activity toward protein tyrosine phosphatase 1B (PTP-1B). Compound 6s was found to be an inhibitor of PTP-1B with nanomolar IC(50) value and high level of selectivity over other recombinant phosphatases.

Facile transformation of 2-azetidinones to 2-piperidones: application to the synthesis of the indolizidine skeleton and (8S,8aS)-perhydro-8-indolizinol.

The highly functionalized bicyclic lactam 7 was prepared from diolefinic-2-piperidone 18 by the use of ruthenium-catalyzed RCM, and in turn, 18 was derived via a two-carbon addition process from readily accessible 4-olefinic-2-azetidinone 13. Bicyclic lactams 7 and 20 could serve as potentially valuable intermediates for the chiral synthesis of various hydroxylated indolizidine alkaloids as exemplified by the synthesis of (8S,8aS)-perhydro-8-indolizinol 19.