Somatostatin peptidomimetics

Bruns C, Lewis i, Briner U, et ai. SOM230 a novei somatostatin peptidomimetic with broad somatotropin reiease inhibiting factor (SRiF) receptor binding and a unique antisecretory profiie. Eur J Endocrinoi 2002 146 707-716. 

A similar scaffold for the preparation of peptidomimetics was prepared by Mitsunobu cyclization of the molecule coming from the coupling of 4-benzylprolinol and iV-nosyl(o-nitrobenzensulfonyl) tryptophan 316 (Scheme 41). A Mitsunobu cyclization occurred easily due to the acidity of the NH of the nosyl group that could be further selectively deprotected under very mild conditions. The so-formed bicyclic amine 317 can be further coupled with different amino acids to give compounds 318, employed in the search of a new somatostatin pharmacophore <2005BML4033>. 

Scheme 32 Glucose p-Turn Peptidomimetic and Somatostatin Analogue 1131...

F ure 3.28. Peptidomimetics that have been designed based on iterative introduction of constraints into parent peptide and hypotheses concerning receptor-bound conformation. Enkephalin mimetic (388), RGD platelet GPIIb/IIIa receptor antagonists (384,385), thyrohberin [TRH (387)], and somatostatin (383,389).For an overview of recent approaches to peptidomimetic design, see the review by Bursavich and Rich (382). 

Peptidomimetics (top) are chemical substitutes for hormones, such as the 14-amino acid peptide hormone somatostatin (bottom). 

L. Maechler, Nonpeptidal peptidomimetics with a beta-D-glucose scaffolding - a partial somatostatin agonist bearing a close structural relationship to a potent, selective substance-P antagonist, J. 

Hirschmann, R., Nicolaou, K.C., ISetranico, S., Salvino, J., Inahy, E.M., et al (1992) Nonpeptidal peptidomimetics with a P-D-glucose scaffolding. A partial somatostatin agonist beating a close stractural relationship to a potent, selective substance P antagonist. J. Am. Chem. Soc. 114 9217-9218. 

Hirschmann, Nicolaou, Smith, and coworkers introduced the use of monosaccharides as privileged structures to modulate receptor and receptor subtype affinities. The P-o-glucose scaffold serves as a nonpeptidal peptidomimetic of the hormone somatostatin (SRIF). Over the past decade, a number of analogs have been synthesized and tested to explore the structure-activity relationships of differential substitution of the sugar core. " In collaboration with Merck researchers, Hirschmann and cowoikers discovered both somatostatin and NK-1 antagonists (Figure 7.2). A small... 

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