Synthesis and structure–activity relationships of oxime neurokinin antagonists: discovery of potent arylamides

Shih, Neng Yang; Albanese, Margaret M.; Anthes, John C.; Carruthers, Nicholas I.; Grice, Cheryl A.; Li, Gang; Mangiaracina, Pietro; Reichard, Gregory A.; Schwerdt, John; Seidl, V.; Wong, Shing‐Chung; Piwinski, John J.

doi:10.1016/s0960-894x(01)00709-0

Cited by 15 publications

(6 citation statements)

References 6 publications

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“…Among other species, optically active 3-aryl-4-pentenoic acid is an important substrate for the synthesis of numerous medicaments such as rolipram, an anti-inflammatory drug and one of the family of γ-aminobutyric acid (GABA) derivatives, as well as citrocard, lioresal, femoxetine, and paroxetine, other drugs belonging to the GABA family . Optically active 3-phenyl-4-pentenoic acid is the key intermediate in the synthesis of LG 121071, a modulator of androgen receptors and neurokinin NK1/NK2 antagonists . ( S )-3-Aryl-4-pentenoic acid derivatives have also been used for the synthesis of antiproliferation lactones (HL-60 cell inhibitors), , antimicrobial agents, and also the antitumor antibiotic methylenolactocin (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Dynamic Kinetic Resolution of 3-Aryl-4-pentenoic Acids

et al. 2016

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The first example of dynamic kinetic resolution (DKR) of chiral unsaturated carboxylic acids is described. The application of tandem metal–enzyme DKR is a powerful tool for the manufacture of high-value chemical commodities. This new protocol of kinetic resolution based on irreversible enzymatic esterification of 3-aryl-4-pentenoic acids with ortho esters was introduced to obtain optically active unsaturated carboxylic acids. This procedure was combined with metal-catalyzed racemization of the target substrate, providing the optically pure S enantiomer of ethyl 3-phenylpent-4-enoate with very high isolated yield (98%). A substantial influence of organic cosolvent and metal catalyst on the conversion and enantioselectivity of the enzymatic dynamic kinetic resolution was noted.

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Section: Introductionmentioning

confidence: 99%

Dynamic Kinetic Resolution of 3-Aryl-4-pentenoic Acids

et al. 2016

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“…The apparently low efficacy of NK1R antagonists in the treatment of pain in humans has been attributed to inadequate clinical trials (84). Alternatively, several dual antagonists of NK1Rs and NK2Rs have been developed (67,77). With the exception of ZD-6021, which has been shown to dose dependently attenuate plasma extravasation in guinea pigs (6), little if any investigation of the therapeutic potential of dual antagonists has been done.…”

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confidence: 99%

Mast cells mediate substance P-induced bladder inflammation through an NK₁receptor-independent mechanism

Saban

Gerard

Saban

et al. 2002

American Journal of Physiology-Renal Physiology

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The role of neurokinin-1 receptors (NK1R) in the interaction between mast cells and substance P (SP) in bladder inflammation was determined. Mast cell-deficient Kit(W)/Kit(W-v), congenic normal (+/+), and Kit(W)/Kit(W-v) mice that were reconstituted with bone marrow cells isolated from NK1R(-/-) mice were challenged by instillation of SP, antigen, or saline into the urinary bladder. Twenty-four hours after challenge, the bladders were prepared for morphological assessment and gene expression. SP-induced bladder inflammation was mast cell dependent and did not require NK1R expression on the mast cell. Cluster analysis identified functionally significant genes that were dependent on the presence of mast cells for their upregulation regardless of stimulus. Those include serine protein inhibitor 2.2, maspin, mitogen- and stress-activated protein kinase 2, and macrophage colony-stimulating factor 1. Our findings demonstrate that while mast cells are essential for both antigen- and SP-induced bladder inflammation, there are common genes and unique genes expressed in each type of inflammatory reaction. When combined with unique animal models, gene array analysis provides a useful approach for identifying and characterizing pathways involved in bladder inflammation.

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“…The oxazoline moiety of the above products should be useful for further transformations 1. For example, hydrolysis of 34 with dilute aqueous acid effected concomitant desilylation (Scheme ) to give a 3‐aryl‐4‐pentenoic acid 39 , which is a known precursor for the synthesis of neurokinin receptor antagonists 15…”

Section: Methodsmentioning

confidence: 99%

Stereoselective Construction of Acyclic Carbon Chains by a One‐Pot Coupling Process Based on Alkenyloxazoline–Titanium Complexes

et al. 2004

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Oxazoline is known as a versatile functional group in organic synthesis for the activation of substrates and for asymmetric synthesis.[1] Complexation of organic compounds having this group with transition metals may lead to the development of unique synthetic transformations, [2] but an olefin complex such as the one in Scheme 1 (M = metal) [3] has not been investigated. We report here that titanation of alkenyloxazolines proceeds nicely to give novel olefin-titanium complexes (Scheme 1, M = Ti(OiPr) 2 ), which subsequently allow for a diastereoselective multicomponent coupling process and an asymmetric coupling reaction. Treatment of alkenyloxazoline 2[4] with a titanium(ii) alkoxide reagent 1 formed from Ti(OiPr) 4 with two equivalents of iPrMgCl, [5] generates olefin complex 3, [6] which underwent a coupling reaction with 1-octyne (4) to give titanacycle 6 (R = C 6 H 13 ; Scheme 2). Intermediates 3 and 6 were identified by deuteriolysis.[7] The carbon-titanium bond a to the oxazoline (rather than the vinyl-titanium bond) of 6 selectively reacted with the octanal to give, after hydrolytic work-up, a single regioisomer 8 having exclusively an Eolefinic bond. Surprisingly, the crude reaction mixture contained this adduct 8 together with a very small amount of one of the four possible diastereoisomers (d.r. = 96:4) arising from the three consecutive stereogenic centers. Compound 8 could be readily separated from this minor isomer [8] by flash chromatography on silica gel to give a pure sample in 66 % yield. The stereochemistry of 8 was determined (as depicted) by derivatization. [7] A stereochemical course from 2 to 8 is proposed in the Supporting Information. [7] Analogously, the sequential treatment of 2 with silylacetylene 5 and nonanal Scheme 1. Generation of the olefin-metal complex.Scheme 2. Four-component coupling process.

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Synthesis and structure–activity relationships of oxime neurokinin antagonists: discovery of potent arylamides

Cited by 15 publications

References 6 publications

Dynamic Kinetic Resolution of 3-Aryl-4-pentenoic Acids

Dynamic Kinetic Resolution of 3-Aryl-4-pentenoic Acids

Mast cells mediate substance P-induced bladder inflammation through an NK₁receptor-independent mechanism

Stereoselective Construction of Acyclic Carbon Chains by a One‐Pot Coupling Process Based on Alkenyloxazoline–Titanium Complexes

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Synthesis and structure–activity relationships of oxime neurokinin antagonists: discovery of potent arylamides

Cited by 15 publications

References 6 publications

Dynamic Kinetic Resolution of 3-Aryl-4-pentenoic Acids

Dynamic Kinetic Resolution of 3-Aryl-4-pentenoic Acids

Mast cells mediate substance P-induced bladder inflammation through an NK1receptor-independent mechanism

Stereoselective Construction of Acyclic Carbon Chains by a One‐Pot Coupling Process Based on Alkenyloxazoline–Titanium Complexes

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Mast cells mediate substance P-induced bladder inflammation through an NK₁receptor-independent mechanism