SOM230: A New Somatostatin Peptidomimetic with Potent Inhibitory Effects on the Growth Hormone/Insulin-Like Growth Factor-I Axis in Rats, Primates, and Dogs

Abstract

The goal of this project was to find a somatostatin (SRIF) analog with superior therapeutic potential. Receptor binding studies of new SRIF analogs were used to reveal SRIF substructures that interact with individual human SRIF receptor subtypes (sst1-sst5). Incorporation of these substructures into a stable cyclohexapeptide template led to SOM230, which binds with nanomolar affinity to sst1, sst2, sst3, and sst5. In rats, the inhibitory effect of SOM230 on GH was similar to SMS 201-995 (octreotide) at 1 h, but was 4-fold more potent at 6 h post injection, indicating increased metabolic stability. Treatment of rats with SOM230, at 1 and 10 micro g/kg.h, decreased IGF-I plasma levels, on d 2, by 68% and 90% (P < 0.01); whereas, under SMS 201-995 treatment, plasma IGF-I levels decreased by 28% and 49%, respectively. After a 2-wk infusion of rats, the suppression of IGF-I levels by SOM230 was still pronounced, whereas the response to SMS 201-995 was largely lost. This enhanced effect of SOM230 on IGF-I plasma levels was confirmed in an 8-wk study where both analogs were infused at 50 micro g/kg/h in rats. In rhesus monkey, SOM230 and SMS 201-995 treatment resulted in GH inhibition, with half-maximal inhibitory dose values of 0.5 and 0.4 micro g/kg, respectively, but plasma IGF-I levels were only lowered by SOM230 (-53%). In cynomolgus monkeys, a 2-wk infusion of SOM230, but to a much lesser extent of SMS 201-995, lowered plasma GH levels significantly (from 16.3 to 1.8 ng/ml, P = 0.007). Both in cynomolgus monkeys and beagle dogs, infusion of SOM230, but not SMS 201-995, lowered IGF-I levels significantly. In conclusion, SOM230 has a unique structure, binds almost universally to human ssts, and inhibits potently the GH/IGF-I axis cross-species. SOM230 is a candidate drug for clinical use.

DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in Octreotide non-responsive tumours

“…Thus, DG3173 may prove to be at least as efficient, as well as even more specific as already existing SSA. In contrast, another new SSA SOM230 with a broad range of sst binding has been shown to substantially inhibit insulin secretion in vivo (14,20,39,40).…”

Function and expression of somatostatin receptors of the endocrine pancreas

“…Standard medical treatment includes octreotide, which acts predominantly via SSTR2 and more recently a panagonist, the peptidomimetic SOM230 which has a 30-40-fold higher binding affinity to SSTR1 and SSTR5 and a more potent long lasting effect on suppression of GH and IGF-I, as compared to octreotide Weckbecker et al, 2002). In humans, both octreotide and SOM230 (transiently) elevated blood glucose levels, however in contrast to octreotide, SOM230 did not inhibit insulin secretion (van der Hoek J. et al, 2004).…”

The role of cortistatin in the human immune system

“…Outside the central nervous system (CNS), both CST and SRIF are present in a variety of neural and nonneural tissues such as pancreas, endocrine tissues and the immune system (Dalm et al, 2004a; de Lecea and Sutcliffe, 1996;de Lecea et al, 1996;Reichlin, 1983a;Reichlin, 1983b). The clinically used SRIF analogues octreotide and lanreotide bind with high and moderate affinity to sst 2 and sst 5 whereas the recently developed synthetic SRIF analog SOM-230 (pasireotide) binds with high affinity to sst 1,2,3 and sst 5 Weckbecker et al, 2002). SOM-230 is currently under clinical investigation.…”