Novel silaproline (Sip)-incorporated close structural mimics of potent antidepressant peptide drug rapastinel (GLYX-13). Issue 16 (19th April 2017)

• Record Type: Journal Article
• Authors: Madica, Krishnaprasad; Nadimpally, Krishna Chaitanya; Sanjayan, Gangadhar J.
• Is Part Of: Tetrahedron letters. Volume 58:Issue 16(2017)
• Page Start: 1568
• Page End: 1571
• Publication Date: 2017-04-19
• Subjects: Rapastinel -- Apimostinel -- Silaproline -- Peptide; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tetlet.2017.03.015
• Languages: English
• ISSNs: 0040-4039

Abstract

Graphical abstract: This paper reports the synthesis of silaproline (Sip)-incorporated close structural mimics of potent antidepressant peptide drug rapastinel (GLYX-13). Highlights: Structural mimics of rapastinel comprising silaproline is reported. Sip introduction is expected to improve its pharmacokinetic profiles. Standard peptide coupling strategy in the solution-phase is utilized for synthesis. Abstract: Rapastinel (GLYX-13) is a C-amidated tetrapeptide drug under clinical development for adjunctive treatment of major depressive disorder (MDD). Rapastinel features two consecutive proline residues centered at the peptide sequence (Thr-Pro-Pro-Thr-NH2 ), which are detrimental to its biological activity. In this communication, we report the synthesis of very close structural analogues of rapastinel comprising silaproline (Sip) as proline surrogate. By virtue of its enhanced lipophilicity and metabolic stability, Sip introduction in the native rapastinel sequence is expected to improve its pharmacokinetic profiles.