Discovery of FR166124, a novel water-soluble pyrazolo-[1,5-α]pyridine adenosine A1 receptor antagonist

Kuroda, Satoru; Akahane, Atsushi; Itani, Hiromichi; Nishimura, Shintaro; Durkin, Kieran; Kinoshita, Takayoshi; Tenda, Yoshiyuki; Sakane, Kazuo

doi:10.1016/s0960-894x(99)00304-2

Cited by 44 publications

(16 citation statements)

References 16 publications

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“…Discovery of FK 838 (18) and FR 166124 (19) has been reported and the importance of the internal double bond of the cyclohexenyl acetic acid moiety in (19) has been proved. Both ligands possess high selectivity over adenosine A 1 receptor and good water solubility as the sodium salts [39]. Further on, it was concluded that in conscious unstressed rats, acute adenosine A 1 receptor inhibition by 18 (6-oxo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1(6H)-pyridazinebutyric acid) led to significant natriuresis caused by inhibition of proximal tubular Na + reabsorption.…”

Section: Non-fused Ringsmentioning

confidence: 99%

Potent Adenosine A1 and A2A Receptors Antagonists: Recent Developments

Yuzlenko

Kieć‐Kononowicz

2006

CMC

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This review summarizes the current tendencies observed in the past 5 years in the development of A(1) and A(2A) adenosine receptor antagonists performed in various academia and industry. A(1) and A(2A) AR antagonists are as well xanthines as heteroaromatic derivatives and are most commonly 6:5 fused heteroatomic compounds. Among xanthine-based compounds, some common features could be pointed out. The recent A(1) AR ligands which show good biological profile, possess long alkyl chains in position 1 and 3 as well as bulky C(8)-substituent, while A(2A) AR antagonists with a high A(2A) AR affinity are C(8)-styryl substituted with N(1)-alkyl/alkynyl moiety or fused tricyclic xanthines possessing heteroatom(s) in the third cycle. The research in the field of heteroaromatic A(1) and A(2A) ARs antagonists impressively has a wide range. Ligands are as well non-fused monocyclic substituted compounds as fused bi- and tricyclic derivatives with the nitrogen, oxygen and sulfur heteroatoms. Most often, adenosine A(1) receptor non-xanthine antagonists are adenine-based, having substituted amino group and variable nitrogen atoms positions in the molecules. A(2A) AR ligands show good affinity when furanyl function, which is crucial for binding, is present in the fused bicyclic and tricyclic analogs. Moreover, tricyclic nitrogen containing antagonists in order to be active, frequently possess long-alkylphenyl moiety.

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Section: Non-fused Ringsmentioning

confidence: 99%

Potent Adenosine A1 and A2A Receptors Antagonists: Recent Developments

Yuzlenko

Kieć‐Kononowicz

2006

CMC

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“…Nevertheless, this derivative had lower binding affinity and poorer selectivity for A 1 receptor than FK453. Subsequently, further structural modifications to FK838 led to the synthesis of FR166124 ( 47 ) [ 49 ], which is the most potent and selective A 1 AR antagonist of this series, and it shows high water solubility (>200 mg/mL). In fact, it was designed based on the hypothesis that the high affinity and selectivity of FK453 for the A 1 receptor was due to the presence of the (2 R )-2-(2-hydroxyethyl)piperidine ring of the acryloyl amide as a conformationally limiting factor.…”

Section: Pyrazolo Derivatives As Potent Ar Antagonistsmentioning

confidence: 99%

Pyrazolo Derivatives as Potent Adenosine Receptor Antagonists: An Overview on the Structure-Activity Relationships

Cheong

Venkatesan

Paira

et al. 2011

International Journal of Medicinal Chemistry

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In the past few decades, medicinal chemistry research towards potent and selective antagonists of human adenosine receptors (namely, A1, A2A, A2B, and A3) has been evolving rapidly. These antagonists are deemed therapeutically beneficial in several pathological conditions including neurological and renal disorders, cancer, inflammation, and glaucoma. Up to this point, many classes of compounds have been successfully synthesized and identified as potent human adenosine receptor antagonists. In this paper, an overview of the structure-activity relationship (SAR) profiles of promising nonxanthine pyrazolo derivatives is reported and discussed. We have emphasized the SAR for some representative structures such as pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines; pyrazolo-[3,4-c] or -[4,3-c]quinolines; pyrazolo-[4,3-d]pyrimidinones; pyrazolo-[3,4-d]pyrimidines and pyrazolo-[1,5-a]pyridines. This overview not only clarifies the structural requirements deemed essential for affinity towards individual adenosine receptor subtypes, but it also sheds light on the rational design and optimization of existing structural templates to allow us to conceive new, more potent adenosine receptor antagonists.

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“…8 In addition, pyrazolo[1,5- a ]pyridine derivatives 2 and 3 (Figure 1) are adenosine A1 receptor antagonists with potent diuretic activity. 9,10…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, they are applicable in the treatment of several neurological disorders including anxiety, schizophrenia, attention deficit disorder, drug dependency, and Parkinson’s disease. − Moreover, members of this family like the pyrazolo[1,5- a ]pyridine derivative 1 (Figure ) has been shown to serve as a potent and selective 5HT3 antagonist, which has been clinically applied to treat vomiting caused by cancer chemotherapy . In addition, pyrazolo[1,5- a ]pyridine derivatives 2 and 3 (Figure ) are adenosine A1 receptor antagonists with potent diuretic activity. , …”

Section: Introductionmentioning

confidence: 99%

Scalable Sonochemical Synthetic Strategy for Pyrazolo[1,5-a]pyridine Derivatives: First Catalyst-Free Concerted [3 + 2] Cycloaddition of Alkyne and Alkene Derivatives to 2-Imino-1H-pyridin-1-amines

2019

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A highly efficient and convenient one-pot sonochemical synthetic strategy has been sophisticated for synthesizing a novel class of polysubstituted pyrazolo[1,5- a ]pyridines via [3 + 2] cycloaddition of dialkyl acetylenedicarboxylates, ethyl propiolate, and alkenes to 2-imino-1 H -pyridin-1-amines under catalyst-free conditions. A series of uniquely substituted pyrazolo[1,5- a ]pyridines has been synthesized with a very good to excellent yield, and the mechanistic pathway that involves a [3 + 2] annulation process was also proposed. In this study, several spectroscopic tools of analyses were employed for structure elucidation, and the X-ray single-crystal technique was utilized to confirm the proposed mechanism and the regioselectivity.

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Discovery of FR166124, a novel water-soluble pyrazolo-[1,5-α]pyridine adenosine A1 receptor antagonist

Cited by 44 publications

References 16 publications

Potent Adenosine A1 and A2A Receptors Antagonists: Recent Developments

Potent Adenosine A1 and A2A Receptors Antagonists: Recent Developments

Pyrazolo Derivatives as Potent Adenosine Receptor Antagonists: An Overview on the Structure-Activity Relationships

Scalable Sonochemical Synthetic Strategy for Pyrazolo[1,5-a]pyridine Derivatives: First Catalyst-Free Concerted [3 + 2] Cycloaddition of Alkyne and Alkene Derivatives to 2-Imino-1H-pyridin-1-amines

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