The discovery of potent, orally bioavailable pyrazolo and triazolopyrimidine CXCR2 receptor antagonists

Porter, David W.; Bradley, Michelle; Brown, Zarin; Canova, Riccardo; Charlton, Steven J.; Cox, Brian J.; Hunt, Peter; Kolarik, David; Lewis, Sarah; O’Connor, Des; Reilly, John M.; Spanka, Carsten; Tedaldi, Lauren; Watson, Simon J.; Wermuth, Roland; Press, Neil J.

doi:10.1016/j.bmcl.2013.11.074

Cited by 21 publications

(14 citation statements)

References 11 publications

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“…In this case, the replacement of the pyrazolopyrimidine core with the TP heterocycle led to selective antagonists with favorable combination of biological and PK properties. [117] In another study, Aghazadeh Tabrizi et al, reported the identification of a TP derivative (76, Table 6) found to act as an inverse agonist of the cannabinoid receptor, CB 2 . [118] In this case, the nature of the substituent at position 2 of the TP scaffold was found to play a crucial role in determining both the inverse agonist activity against the CB 2 receptor, as well as the selectivity of CB 2 /CB 1 .…”

Section: Miscellaneousmentioning

confidence: 99%

1,2,4-Triazolo[1,5-a]pyrimidines in drug design

Oukoloff

Lucero

Francisco

et al. 2019

European Journal of Medicinal Chemistry

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The 1,2,4-triazolo [1,5-a]pyrimidine (TP) heterocycle, in spite of its relatively simple structure, has proved to be remarkably versatile as evidenced by the many different applications reported over the years in different areas of drug design. For example, as the ring system of TPs is isoelectronic with that of purines, this heterocycle has been proposed as a possible surrogate of the purine ring. However, depending on the choice of substituents, the TP ring has also been described as a potentially viable bio-isostere of the carboxylic acid functional group and of the N-acetyl fragment of ε-N-acetylated lysine. In addition, the metal-chelating properties of the TP ring have also been exploited to generate candidate treatments for cancer and parasitic diseases. In the present review article, we discuss recent applications of the TP scaffold in medicinal chemistry, and provide an overview of its properties and methods of synthesis.

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Section: Miscellaneousmentioning

confidence: 99%

1,2,4-Triazolo[1,5-a]pyrimidines in drug design

Oukoloff

Lucero

Francisco

et al. 2019

European Journal of Medicinal Chemistry

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“…They are also used as CXCR2 receptor [23] and adenosine A 2a receptor antagonist [24]. Some of the recently chemical syntheses of various derivatives of triazolopyrimidines have also been reported via treatment of 3-amino-1,2,4-triazole with ethylacetoacetate under acidic conditions [25] or the reaction of 5-amino-3-morpholino-1H-1,2,4-triazole with diethyl ethoxymethylenemalonate in glacial acetic acid [26].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, triazolopyrimidines are another important class of heterocyclic compounds that have been reported as active as antimycobacterial , herbicidal , antitumor and anti‐inflammatory . They are also used as CXCR2 receptor and adenosine A 2a receptor antagonist . Some of the recently chemical syntheses of various derivatives of triazolopyrimidines have also been reported via treatment of 3‐amino‐1,2,4‐triazole with ethylacetoacetate under acidic conditions or the reaction of 5‐amino‐3‐morpholino‐1H‐1,2,4‐triazole with diethyl ethoxymethylenemalonate in glacial acetic acid .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Oxazolo[5,4‐d][1,2,4]triazolo[4,3‐a]pyrimidines as a New Class of Heterocyclic Compounds

Akbarzadeh

Bakavoli

Shiri

2015

Journal of Heterocyclic Chem

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Several new derivatives of oxazolo [5,4-d]pyrimidine (3a-h) have been synthesized through the reaction of 2,4-dichloro-6-methyl-5-nitropyrimidine (2) with aryl carboxylic acids in refluxing POCl 3 . Further treatment of compounds (3a-h) with hydrazine hydrate gave the hydrazine derivatives (4a-h) that were subsequently cyclized into a novel heterocyclic system, oxazolo [5,4-d][1,2,4]triazolo[4,3-a]pyrimidine (5a-p) and (7a-d) on treatment with triethylorthoesters or carbondisulfide and alkylhalides, respectively. H NMR (CDCl 3 ): δ 2.89 (s, 3H, CH 3 of pyrimidine), 7.45 (t, J = 7.4 Hz, 1H, 2-chlorophenyl), 7.53 (t, J = 7.4 Hz, 1H, 2-chlorophenyl), 7.58 (d, J = 8.0 Hz, 1H, 2-chlorophenyl), 8.14 (d, J = 7.6 Hz, 1H, 2-chlorophenyl); 13 C NMR (CDCl 3 ): δ 165.2, 162.7, 160.7, 155.2, 834

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“…2 Dompé’s ketoprofen derivative reparixin 4 , an inhibitor of CXCL8 receptor CXCR1 and CXCR2 activation, 27,28 is being explored for the reduction of post-surgical inflammation after transplantation surgeries. 2 Novartis 29,30 and Pfizer 23,31 also have active CXCR2 programs.…”

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confidence: 99%

Boronic acid-containing aminopyridine- and aminopyrimidinecarboxamide CXCR1/2 antagonists: Optimization of aqueous solubility and oral bioavailability

Schuler

Engles

Maeda

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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The chemokine receptors CXCR1 and CXCR2 are important pharmaceutical targets due to their key roles in inflammatory diseases and cancer progression. We have previously identified 2-[5-(4-Fluoro-phenylcarbamoyl)-pyridin-2-ylsulfanylmethyl]-phenylboronic acid (SX-517) and 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide (SX-576) as potent non-competitive boronic acid-containing CXCR1/2 antagonists. Herein we report the synthesis and evaluation of aminopyridine and aminopyrimidine analogues of SX-517 and SX-576, identifying (2-{(Benzyl)[(5-boronic acid-2-pyridyl)methyl]amino}-5-pyrimidinyl)(4-fluorophenylamino)formaldehyde as a potent chemokine antagonist with improved aqueous solubility and oral bioavailability.

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The discovery of potent, orally bioavailable pyrazolo and triazolopyrimidine CXCR2 receptor antagonists

Cited by 21 publications

References 11 publications

1,2,4-Triazolo[1,5-a]pyrimidines in drug design

1,2,4-Triazolo[1,5-a]pyrimidines in drug design

Synthesis of Oxazolo[5,4‐d][1,2,4]triazolo[4,3‐a]pyrimidines as a New Class of Heterocyclic Compounds

Boronic acid-containing aminopyridine- and aminopyrimidinecarboxamide CXCR1/2 antagonists: Optimization of aqueous solubility and oral bioavailability

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