title: Novel malonamide derivatives as alpha v beta 3 antagonists. Syntheses and evaluation of 3-(3-indolin-1-yl-3-oxopropanoyl)aminopropanoic acids on vitronectin interaction with alpha v beta 3.
abstract: In attempt to find novel integrin alphavbeta3 antagonists, we selected SC65811 and its guanidine analogue (1) as lead compounds. Modification of the glycine part of SC65811 led to a new series of malonamide derivatives that exhibited alphavbeta3 inhibitory activity. Among them, (R,S)-3-[3-[6-(3-benzylureido)indolin-1-yl]-3-oxopropanoylamino]-3- (pyridin-3-yl)propanoic acid (43a) showed not only potent activity with an IC50 value of 3.0 nM but also good selectivity for alphavbeta3 relative to alphaIIbbeta3, alpha5beta1, and alphavbeta5 with IC50 values of 19,000, 11,000, and 14 nM, respectively. Furthermore, optimization of 43a led to the most potent alphavbeta3 antagonist, (R,S)-3-(3-[6-[(4,5-dihydro-1H-imidazol-2-yl)amino]indolin-1-yl]-3-oxopropanoylamino)-3-(quinolin-3-yl)propanoic acid (431) with an IC50 value of 0.42 nM. The synthesis and the structure-activity relationships of these malonamide derivatives are presented.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co Ltd, Tsukuba, Ibaraki Japan. nagashim@yamanouchi.co.jp
authors.forename: S
authors.initials: S
authors.lastname: Nagashima
authors.forename: S
authors.initials: S
authors.lastname: Akamatsu
authors.forename: E
authors.initials: E
authors.lastname: Kawaminami
authors.forename: S
authors.initials: S
authors.lastname: Kawazoe
authors.forename: T
authors.initials: T
authors.lastname: Ogami
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: M
authors.initials: M
authors.lastname: Okada
authors.forename: K I
authors.initials: KI
authors.lastname: Suzuki
authors.forename: S I
authors.initials: SI
authors.lastname: Tsukamoto
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008314:Malonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D003432:Cross-Linking Reagents; D008314:Malonates; D019030:Receptors, Vitronectin; C402424:SC 65811; C008314:malonamide