Pasireotide is a cyclic hexapeptide that was discovered using a rational approach to design a stable somatostatin analog with a receptor selectivity profile resembling that of native somatostatin. Pasireotide (Fig. 2c), has high affinity for sstr1,2,3 and 5 (Table 1), with much higher affinity for subtypes 1 and 5, and lower affinity for subtype 2, compared with octreotide [40]. In preclinical studies, pasireotide demonstrated inhibition of ACTH secretion in cultured human corticotroph adenomas [19, 20] and in murine AtT20 cells [17, 19]; one study has also reported reduced cell proliferation in cultured human corticotropinomas [20]. Compared with octreotide, pasireotide demonstrated greater suppression of CRH-stimulated ACTH release from AtT20cells [17, 19]. Further, consistent with the model of glucocorticoid-mediated downregulation of sstr2, pretreatment of AtT20 cells with dexamethasone abolished the inhibitory effects of octreotide on ACTH secretion, but had no effect on the inhibitory action of pasireotide or somatostatin-14 [33]. Together, these findings support the conclusion that pasireotide inhibits ACTH secretion from corticotroph adenomas by acting predominantly at sstr5. Subsequent supportive in vivo results [41, 42] established the rationale for studies on the use of pasireotide in patients with CD.