Design and synthesis of potent and selective 1,3,4-trisubstituted-2-oxopiperazine based melanocortin-4 receptor agonists

Mastering chiral substituted 2-oxopiperazines

“…33 Studies directed toward the development of a short and efficient route for the preparation of piperazinone 136, 97 led to the discovery of the synthetic pathway outlined in Scheme 55.…”

“…33,70,[95][96][97] This approach usually takes place via a two-step sequence involving an initial intermolecular N 4 -C 5 bondforming reaction followed by an intramolecular C 6 -N 1 bond-forming step. The reaction of dipeptide 122 with ethylene glycol bis-triflate gives 2-oxopiperazine 268 (Scheme 52), 70 while other 1,2-dielectrophiles, such as ethylene sulfate, were completely uneffective.…”

“…Excellent examples of peptidomimetic drugs discovered using a 2-oxopiperazine template that conformationally mimics the dipeptide moiety include constrained substance P analogues, 23 farnesyltransferase (FTase) 24 and protein geranylgeranyltransferase-I (PGGTase-I) 25 inhibitors, compounds with dual farnesyltransferase/geranylgeranyltransferase-I inhibitory activity, 26 elastase, 27 factor Xa, 28 renin [29][30][31] and BACE1 32 inhibitors, melanocortin receptors (MCRs) agonists, 33 fibrinogen glycoprotein IIb-IIIa, 34,35 and neuropeptide S (NPS) receptor 36,37 antagonists.…”

New efficient enantioselective synthesis of 2-oxopiperazines: a practical access to chiral 3-substituted 2-oxopiperazines

“…1 Moreover, these azalactams have significant potential as cancer chemotherapeutic agents, 2,3 and are promising candidates for the treatment and prevention of diverse diseases such as rheumatoid arthritis, 4 depression, 5 sexual disfunctions 6 or venous and arterial thrombosis. 7 In some cases, the oxopiperazine core is used as a conformationally constrained peptidomimetic in which the N i and N i+1 positions of the peptide backbone fragments are linked by an ethylene bridge.…”

Synthesis of Diphenylmethyl Analogues and Their Affinity for the Melanocortin-4 Receptor and the Serotonin Transporter

“…[4][5][6][7][8][9][10][11][12][13] In addition, this receptor has been the focus of interest for its possible relationship to stress and the regulation of emotional behavior [14][15][16] in relation to conditions such as depression and anxiety. [17][18][19][20] The findings to date indicate that the MC4 receptor may be a promising target for the development of drugs for the abovementioned conditions, and numerous agonists [25][26][27][28][29] and antagonists [22][23][24][30][31][32][33][34][35][36][37][38][39][40] of the MC4 receptor have been developed. We previously reported that the MC4 receptor antagonist 3 (MCL0129; Fig.…”