title: Studies on neurokinin antagonists. 4. Synthesis and structure-activity relationships of novel dipeptide substance P antagonists: N2-[(4R)-4-hydroxy-1-[(1-methyl-1H-indol-3-yl)carbonyl]-L-prolyl]-N- methyl-N-(phenylmethyl)-3-(2-naphthyl)-L-alaninamide and its related compounds.
abstract: As an extension of our studies on discovering a novel substance P (SP) antagonist, we modified the previously reported dipeptide, N2-[N2-(1H-indol-3-ylcarbonyl)-L-lysyl]-N-methyl-N-(phenyl-methyl) -L- phenylalaninamide (2b). The lysine part in 2b was first optimized to a (2S,4R)-hydroxyproline derivative (3h), which is 2-fold more potent than 2b in [3H]SP binding assay using guinea pig lung membranes. Next we modified the 1H-indol-3-ylcarbonyl part in 3h. Introduction of a methyl group at the indole nitrogen enhanced the oral activity, while retaining the binding activity. Finally, we modified the phenylalanine part to culminate in the most potent compound 7k (FK888), which is a potent SP antagonist with NK1 selectivity as well as oral activity.
authors.affiliation: New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Hagiwara
authors.forename: H
authors.initials: H
authors.lastname: Miyake
authors.forename: N
authors.initials: N
authors.lastname: Igari
authors.forename: M
authors.initials: M
authors.lastname: Karino
authors.forename: Y
authors.initials: Y
authors.lastname: Maeda
authors.forename: T
authors.initials: T
authors.lastname: Fujii
authors.forename: M
authors.initials: M
authors.lastname: Matsuo
mesh_terms: D000818:Animals; D001665:Binding Sites; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D011654:Pulmonary Edema / Q000139:chemically induced / Q000188:drug therapy; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000633:toxicity
chemical_list: D004151:Dipeptides; D007211:Indoles; C078949:FK 888; D013373:Substance P