Combinatorial synthesis and biological evaluation of peptide-binding GPCR-targeted library.
As an effective strategy of the drug discovery for peptide-binding GPCRs based on the natural ligands, beta-turn peptidomimetic compound library with benzodiazepine skeleton was constructed using solid and solution phase parallel synthesis with four different scaffolds containing Phe, Lys, Ser and Glu, respectively. The usefulness of 162 library compounds was evaluated by the cell based screening at melanocortin 4 receptor in CHO-k1 cells, to find hit compounds showing agonistic effect at the receptor. The screening of library afforded three hit compounds including the most effective analog, (S)-3-benzyl-7-(4-fluorobenzyloxy)-4-(4-methoxyphenethyl)-4,5-dihydro-1H-benzo[e][1,4]diazepin-2(3H)-one, 13aiE, of which EC(50) was determined as 13 microM.
Lee
Ju Yeon
JY
Department of Life Science, Gwangju Institute of Science and Technology, 1 Oryong-dong, Buk-gu, Gwangju 500-712, Republic of Korea.
Im
Isak
I
Webb
Thomas R
TR
McGrath
Douglas
D
Song
Mi-Ryoung
MR
Kim
Yong-Chul
YC
D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery; D010455:Peptides / Q000737:chemistry*; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000378:metabolism
C542505:(S)-3-benzyl-7-(4-fluorobenzyloxy)-4-(4-methoxyphenethyl)-4,5-dihydro-1H-benzo(e)(1,4)diazepin-2(3H)-one; D001381:Azepines; D010455:Peptides; D044105:Receptor, Melanocortin, Type 4