Non-peptidic αvβ3 antagonists containing indol-1-yl propionic acids

Leonard, Kristi; Pan, Wenxi; Anaclerio, Beth; Gushue, Joan M.; Guo, Zihong; DesJarlais, Renée L.; Chaikin, Marge A.; Lattanze, Jennifer; Crysler, Carl; Manthey, Carl L.; Tomczuk, Bruce E.; Marugán, Juan

doi:10.1016/j.bmcl.2005.01.028

Cited by 26 publications

(14 citation statements)

References 16 publications

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“…Several indol-1-yl propionic acids, containing a variety of basic moieties at the 5-position as well as substitutions alpha and beta to the carboxy terminus, were reported [78]. The most active compound 12 carries a 3-pyridyl substituent on the carboxylic chain and a tetrahydronaphthyridine moiety at the 5-position of the indole ring.…”

Section: Non Peptidicmentioning

confidence: 98%

Small Molecule Integrin Antagonists in Cancer Therapy

Paolillo¹,

Russo²,

Serra³

et al. 2009

MRMC

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Integrins are a large family of dimeric receptors composed by alpha and beta subunits that, once bound to extra-cellular matrix (ECM) proteins, regulate a variety of cellular processes such as cell motility, migration, and proliferation. The integrins transduce signals from inside-out and outside-in the cell, thus representing the cellular link to the external environment. For these properties, integrin activation has been involved in pathological processes like tumor growth and metastasis formation. Recent advances in the elucidation of the crystallographic structures of the alphavbeta3 and alphaIIbeta3 integrins are promoting studies focused to the search of small molecule antagonists that can block the integrin binding to ECM and inhibit the biological effects exerted by these receptors. In this review we will focus on small molecule antagonists of alphavbeta3 and alphavbeta5 integrin as tools for cancer therapy while other integrins will only be briefly mentioned. Cilengitide (cyclic peptidic alphavbeta3 and alphavbeta5 antagonist) is currently in clinical trials for anti cancer therapy. Combination of integrin alphavbeta3 antagonists and other traditional therapeutic approaches may represent a future strategy to inhibit tumor growth and metastasis spreading.

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Section: Non Peptidicmentioning

confidence: 98%

Small Molecule Integrin Antagonists in Cancer Therapy

Paolillo¹,

Russo²,

Serra³

et al. 2009

MRMC

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“…TDP223206 was a non-peptidic a v b 3 antagonist with an oral bioavailability of 73% in mice PK studies [18]. The bioavailability in rats was 32.95% at 10 mg/kg and 24.46% at 50 mg/kg, which was much lower than that in mice, indicating the species difference.…”

Section: Pk Profiles Following Intravenous Administrations Of Tdp223206mentioning

confidence: 98%

“…TDP223206 is a non-peptidic a v b 3 antagonist with an oral bioavailability of 73% in mice PK studies [18].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of TDP223206 following intravenous and oral administration to intact rats and intravenous administration to bile duct‐cannulated rats

Chen

Cheng

Marugán³

et al. 2008

Biopharm & Drug Disp

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The pharmacokinetics of TDP223206 was studied following single intravenous and oral administrations in rats. A mixture of TDP223206 and (14)C-TDP223206 were administered to intact and bile duct-cannulated rats. Following intravenous administration, plasma concentrations declined biphasically. The AUC(inf) increased linearly with dose but was not dose proportional. The PK parameters of TDP223206 indicated low clearance (254-386 ml/h/kg) and a moderate volume of distribution (968-1883 ml/kg). The bioavailability was 32.95% and 24.46% for 10 and 50 mg/kg oral doses, respectively. (14)C-TDP223206 was distributed widely into different tissues with small intestine, liver, kidneys and large intestine having large tissue to plasma ratios. (14)C-TDP223206 was the major circulating component in the plasma. A total of 91.2% of administered radioactivity of (14)C-TDP223206 was recovered in bile indicating that biliary excretion was the major pathway for drug elimination. (14)C-TDP223206-acyl glucuronides were the major metabolites in bile. The oxo-(14)C-TDP223206 was the major metabolite in plasma and an important metabolite in bile. Two forms of diastereomeric acyl glucuronides of (14)C-TDP223206 were detected in bile with similar LC/MS intensities suggesting a similar biotransformation capacity. Only one form of these (14)C-TDP223206-acyl glucuronides was detected in plasma suggesting that enterohepatic recirculation was related to the nature of the stereo-isomers.

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“…[10] Sequential hydroboration and oxidation of N-allylindole 5q and then oxidation of the alcohol with iodobenzene diacetate, TEMPO, and sodium bicarbonate led to (R)-3-(3-(methoxycarbonyl)-1H-indol-1-yl)-3-phenylpropanoic acid (14) in 79% yield over two steps.…”

Section: Within the Past Five Years Molecular Scaffolds Containing 3mentioning

confidence: 99%

“…The enantioenriched products are readily converted into monoamine reuptake inhibitors, [9] the indole core of integrin α v β 3 inhibitors, [10] and highly substituted dihydropyrrolo [1,2-a]indoles.…”

Section: Introductionmentioning

confidence: 99%

Iridium‐Catalyzed Regio‐ and Enantioselective N‐Allylation of Indoles

Stanley

Hartwig

2009

Angewandte Chemie

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Keywordsallylation; asymmetric catalysis; heterocycles; iridium; synthetic methods Chiral indole architectures are present in a wide variety of natural products and have been identified as promising lead compounds in medicinal chemistry.[1] Therefore, extensive effort has been dedicated to synthesizing enantioenriched indole derivatives by catalytic, enantioselective reactions,[2] such as 1,2-additions to carbonyl compounds and imines, [3] additions to electron-deficient alkenes, [4] and allylation reactions.[5] However, the indole acts as a carbon nucleophile in each of these reactions; catalytic, enantioselective reactions at the nitrogen atom of an indole are rare, but would provide access to an array of enantioenriched, heterocyclic architectures.One approach to overcome the greater nucleophilicity of the C3-position of indole, relative to that of N1, is to install an electron-withdrawing substituent at C2. Such a substituent tempers the nucleophilicity at C3, increases the acidity of the N-H bond, and can be used either for additional transformations or removed after reaction at the nitrogen center. Even by following this approach, catalytic, enantioselective reactions of indoles at the nitrogen center are rare. Recent reports by Bandani et al. [6] and Chen et al. [7] have shown that asymmetric alkylation of the indole nitrogen atom occurs with modified cinchona alkaloids, but just one report of enantioselective reactions catalyzed by a transition-metal complex that occur at an indole nitrogen atom has been published. In this work, N-substituted indolopyrrolocarbazole derivatives were synthesized by palladium-catalyzed asymmetric allylic alkylation of bis (indole) lactam pro-aglycons. [8] The potential of enantioselective N-allylation of indoles to create an entry into biologically active indole derivatives, particularly with catalysts that preferentially form chiral, branched products from linear allylic esters, led us to investigate iridium-catalyzed, asymmetric, Nallylation of indoles. We report herein the synthesis of enantioenriched, branched Nallylindoles from the reactions of 2-subsituted, 3-substituted, and 2,3-disubstituted indoles with achiral linear allylic carbonates in the presence of a single-component iridium catalyst [Eq.(1)]. The enantioenriched products are readily converted into monoamine reuptake inhibitors, [9] the indole core of integrin α v β 3 inhibitors, [10] and highly substituted dihydropyrrolo [1,2-a]indoles.

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Non-peptidic αvβ3 antagonists containing indol-1-yl propionic acids

Cited by 26 publications

References 16 publications

Small Molecule Integrin Antagonists in Cancer Therapy

Small Molecule Integrin Antagonists in Cancer Therapy

Pharmacokinetics of TDP223206 following intravenous and oral administration to intact rats and intravenous administration to bile duct‐cannulated rats

Iridium‐Catalyzed Regio‐ and Enantioselective N‐Allylation of Indoles

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