Biological Role of HSL

Insulin, a hormone associated with the parasympathic nervous system, has the opposite effect. It decreases the intracellular level of c-AMP. Under these conditions PKA is deactivated and HSL is dephosphorylated by the corresponding phosphatase. Lipolysis in adipocytes is blocked and the amount of NEFAs available for -oxidation is reduced. At the same time lipogenesis is activated by the stimulation of cAMP-independent kinases, which phosphorylate and activate acetyl-Co carboxylase. 

HSL activity was first identified in 1964 as an epinephrine-sensitive lipolytic activity in adipose tissue. It was named according to its property of being activated by hormones such as catecholamines, ACTH, and glucagon [29]. In 1981 the isolation of a relatively pure and biologically active HSL from rat adipocytes was reported [30]. The first cDNA clones were isolated for both rat and human HSL in 1988 [31] and the gene sequence for human HSL was elucidated in 1993 [32]. 

Several inhibitors of lipases have been described (for a review see Patkar et al. [45]). HSL was first described in 1964, but it was not until 2000 that the first inhibitors were reported. Several companies have recently investigated HSL inhibitors to treat diabetes and lipid disorders. In 2000 Alteon [46] published a patent on eu-desmannolides, a natural product isolated from Ivoa microcephala nut. One year later Aventis [47] reported a series of natural products from Streptomyces called cy-clipostines. In the same year Aventis [48] and Novo Nordisk [49] published the first synthetic HSL inhibitors (3,4-dihydro-lH-isoquinolin-2-yl)carbamates, Novo Nordisk, and 3-phenyl-5-alkoxy-l,3,4-oxadiazol-2-ones, Aventis. In 2003, Ontogene [50] described pyrrolopyrazinediones and Novo Nordisk [51] reported another class 

For the first cycles we left the oxadiazolone moiety unchanged and focused on optimizing the R2-part of the molecule in Fig. 7.4. We were interested which type of hydrophobic interactions favors inhibition of HSL. Therefore, we selected R2 substituents with different aliphatic, aromatic, and alicyclic moieties. Only aromatic moieties provoked a reasonable activity. For example, 4 is inactive, whereas 

Both meta- and para-substitutions on the phenyl ring are well tolerated (6, 7), whereas ortho-substitution seems to hamper biological activity (8). 

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