Identification of trans-4-[1-[[7-fluoro-2-(1-methyl-3-indolyl)-6-benzoxazolyl]acetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid as a potent, orally active VLA-4 antagonist

Setoguchi, Masaki; Iimura, Soshi; Sugimoto, Yuuichi; Yoneda, Yasuko; Chiba, Jun; Watanabe, Toshiyuki; Muro, Fumihito; Iigo, Yutaka; Takayama, Gensuke; Yokoyama, Mika; Taira, Tomoe; Aonuma, Misato; Takashi, Tohru; Nakayama, Atsushi; Machinaga, Nobuo

doi:10.1016/j.bmc.2011.12.045

Cited by 13 publications

(10 citation statements)

References 33 publications

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“…The alteration of placing fluorine in the lipophilic moiety, made the compound easier to use with a certain serum protein as carrier, thus resulting in a high serum concentration. It also has excellent efficacy in a bronchial inflammatory model and favorable PK profile [ 147 ].…”

Section: Benzazolesmentioning

confidence: 99%

Importance of Fluorine in Benzazole Compounds

2020

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Fluorine-containing heterocycles continue to receive considerable attention due to their unique properties. In medicinal chemistry, the incorporation of fluorine in small molecules imparts a significant enhancement their biological activities compared to non-fluorinated molecules. In this short review, we will highlight the importance of incorporating fluorine as a basic appendage in benzothiazole and benzimidazole skeletons. The chemistry and pharmacological activities of heterocycles containing fluorine during the past years are compiled and discussed.

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Section: Benzazolesmentioning

confidence: 99%

Importance of Fluorine in Benzazole Compounds

2020

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“…trans ‐4‐(1‐{[2‐(5‐Fluoro‐2‐methylphenylamino)‐7‐fluoro‐6‐benzoxazolyl]acetyl}‐(5 S )‐[methoxy(methyl)amino]methyl‐(2 S )‐pyrrolidinylmethoxy)cyclohexanecarboxylic acid ( 273 ; Figure ) was discovered by Daiichi Sankyo in 2013 as a potent, orally active, very late antigen‐4 (VLA‐4) antagonist for the treatment of asthma . This molecule incorporates an embedded proline moiety and two fluorinated aromatic rings.…”

Section: Cyclic Aasmentioning

confidence: 99%

“…The synthesis of compound 273 is presented in Scheme . A Mitsunobu reaction between ethyl 4‐hydroxybenzoate and (2 S ,5 S )‐ tert ‐butyl 2‐[(benzyloxy)methyl]‐5‐(hydroxymethyl)pyrrolidine‐1‐carboxylate ( 274 ) in the presence of Ph 3 P/DIAD afforded ether 275 , which was subjected to a sequence of Pd‐catalyzed deprotection of the benzyl moiety, CF 3 CO 2 H‐promoted deprotection of the Boc group, hydrogenative reduction of the phenyl ring to cyclohexane, and protection with a Boc group, resulting in cis ‐disposed intermediate 276 .…”

Section: Cyclic Aasmentioning

confidence: 99%

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

Mei

Han

White

et al. 2020

Chemistry A European J

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Structural analysis of modern pharmaceutical practices allows for the identification of two rapidly growing trends: the introduction of tailor‐made amino acids and the exploitation of fluorinated motifs. Curiously, the former represents one of the most ubiquitous classes of naturally occurring compounds, whereas the latter is the most xenobiotic and comprised virtually entirely of man‐made derivatives. Herein, 39 selected compounds, featuring both of these traits in the same molecule, are profiled. The total synthesis, source of the corresponding amino acids and fluorinated residues, and medicinal chemistry aspects and biological properties of the molecules are discussed.

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“…Increased bioavailability was obtained by Daiichi Sankyo Ltd. researchers by linking fluoro-prolinol derivatives to halogen or alkyl substituted aromatic PUPA fragment (Muro et al, 2009). Benzoic or cyclohexanecarboxylic acids were introduced in this class of compounds as metal binding pharmacophores (Setoguchi et al, 2012). Modifications to the polar surface and the number of hydrogen bonds by changing PUPA with other lipophilic groups has also been explored (Setoguchi et al, 2013).…”

Section: Small Molecules Targeting α4β1 Integrinmentioning

confidence: 99%

Novel Ligands Targeting α4β1 Integrin: Therapeutic Applications and Perspectives

et al. 2019

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Among the other members of the adhesion molecules' family, α 4 β 1 integrin, a heterodimeric receptor, plays a crucial role in inflammatory diseases, cancer development, metastasis and stem cell mobilization or retention. In many cases, its function in pathogenesis is not yet completely understood and investigations on ligand binding and related stabilization of active/inactive conformations still represent an important goal. For this reason, starting from the highlight of α 4 β 1 functions in human pathologies, we report an overview of synthetic α 4 β 1 integrin ligands under development as potential therapeutic agents. The small molecule library that we have selected represents a collection of lead compounds. These molecules are the object of future refinement in academic and industrial research, in order to achieve a fine tuning of α 4 β 1 integrin regulation for the development of novel agents against pathologies still eluding an effective solution.

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Identification of trans-4-[1-[[7-fluoro-2-(1-methyl-3-indolyl)-6-benzoxazolyl]acetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid as a potent, orally active VLA-4 antagonist

Cited by 13 publications

References 33 publications

Importance of Fluorine in Benzazole Compounds

Importance of Fluorine in Benzazole Compounds

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

Novel Ligands Targeting α4β1 Integrin: Therapeutic Applications and Perspectives

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