A Novel Somatostatin Mimic with Broad Somatotropin Release Inhibitory Factor Receptor Binding and Superior Therapeutic Potential

Abstract

A rational drug design approach, capitalizing on structure-activity relationships and involving transposition of functional groups from somatotropin release inhibitory factor (SRIF) into a reduced size cyclohexapeptide template, has led to the discovery of SOM230 (25), a novel, stable cyclohexapeptide somatostatin mimic that exhibits unique high-affinity binding to human somatostatin receptors (subtypes sst1-sst5). SOM230 has potent, long-lasting inhibitory effects on growth hormone and insulin-like growth factor-1 release and is a promising development candidate currently under evaluation in phase I clinical trials.

Novel sst2-Selective Somatostatin Agonists. Three-Dimensional Consensus Structure by NMR

“…The long range medium NOE observed between DPhe 2 (NH) and Thr 10 (HN) as well as the strong αH NOE observed between the cysteins stabilize the structure. The side chain of DPhe 2 is in the gauche + rotamer, Aph 7 and DTrp 8 are in the trans rotamer and that of Lys 9 is in the gauche − rotamer (Table 4). Analogue 4 binds selectively with nanomolar affinity to the sst 2 receptor.…”

Expression, pharmacology, and functional role of somatostatin receptor subtypes 1 and 2 in human macrophages

“…Because of their long-acting properties in vitro and in vivo, low molecular weight/metabolically stable analogs are more suitable for clinical application or experimental investigations than SRIF-14 [2,41]. Among synthetic ligands, we used the peptidyl multiligand analog SOM230, which binds with high affinity to sst 1,2,3,5 [42][43][44], and the peptidyl multiligand analog KE108, which binds with high affinity to all five SRIF receptors [44,45]. The sst 1 -selective peptidyl agonist CH-275 [35,41,46,47], the sst 2 -preferring peptiydyl agonist SMS 201-995 (also known as sandostatin or octreotide) [38,41,46,48,49], and the sst 2 -selective nonpeptidyl agonist L-779,976 [46, 49 -51] were also used in the absence or presence of the sst 1 -selective nonpeptydil antagonist SRA-880 [46,52,53] and the sst 2 -selective peptydil antagonist CYN [36,38,48,49,54].…”

Physiology and pathology of somatostatin in the mammalian retina: A current view

“…SRIF analogues are either peptidic or non-peptidic compounds that equally bind to the majority of SRIF receptors (Armani et al, 2007;Ludvigsen et al, 2007;Nolan et al, 2007;Zatelli et al, 2007;Batista et al, 2006;Cervia et al, 2005a;van der Hoek et al, 2005;van der Hoek et al, 2004;Lewis et al, 2003;Reubi et al, 2002), or are selective for a specific SRIF receptor subtype or class (Cervia et al, 2005b;Olias et al, 2004;Weckbecker et al, 2003). In addition, the emergence of novel multispecific SRIF analogues (compounds targeting different cellular receptors) and conjugates (synthesised by chemically linking SRIF analogues with other agents) with improved receptor specificity may produce a new generation of potential drugs (Dasgupta, 2004).…”