- Synthesis and utility of 2-halo-O6-(benzotriazol-1-yl)- functionalized purine nucleosides
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An efficient synthesis of 2-halo-O6-(benzotriazol-1-yl)- substituted purine nucleosides has been accomplished via (benzotriazol-1-yloxy) tris(dimethylamino)phosphonium hexafluorophosphate (BOP)-mediated coupling and subsequent halogenation via diazotization of the 2-amino group of various protected guanosines and directly from guanosine itself. These products are amenable to substitution and coupling reactions in the 2- and 6-positions and, accordingly, provide efficient access to highly functionalized purine nucleosides.
- Devine, Shane M.,Scammells, Peter J.
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- Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors
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Solid tumors are often associated with high levels of extracellular ATP. Ectonucleotidases catalyze the sequential hydrolysis of ATP to adenosine, which potently suppresses T-cell and NK-cell functions via the adenosine receptors (A2a and A2b). The ectonucleotidase CD73 catalyzes the conversion of AMP to adenosine. Thus, increased CD73 enzymatic activity in the tumor microenvironment is a potential mechanism for tumor immune evasion and has been associated with poor prognosis in the clinic. CD73 inhibition is anticipated to restore immune function by skirting this major mechanism of adenosine generation. We have developed a series of potent and selective methylenephosphonic acid CD73 inhibitors via a structure-based design. Key binding interactions of the known inhibitor adenosine-5′-(α,β-methylene)diphosphate (AMPCP) with hCD73 provided the foundation for our early designs. The structure-activity relationship study guided by this structure-based design led to the discovery of 4a, which exhibits excellent potency against CD73, exquisite selectivity against related ectonucleotidases, and a favorable pharmacokinetic profile.
- Sharif, Ehesan U.,Kalisiak, Jaroslaw,Lawson, Kenneth V.,Miles, Dillon H.,Newcomb, Eric,Lindsey, Erick A.,Rosen, Brandon R.,Debien, Laurent P. P.,Chen, Ada,Zhao, Xiaoning,Young, Stephen W.,Walker, Nigel P.,Str?ter, Norbert,Scaletti, Emma R.,Jin, Lixia,Xu, Guifen,Leleti, Manmohan R.,Powers, Jay P.
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p. 845 - 860
(2021/02/05)
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- Discovery of AB680: A Potent and Selective Inhibitor of CD73
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Extracellular adenosine (ADO), present in high concentrations in the tumor microenvironment (TME), suppresses immune function via inhibition of T cell and NK cell activation. Intratumoral generation of ADO depends on the sequential catabolism of ATP by two ecto-nucleotidases, CD39 (ATP → AMP) and CD73 (AMP → ADO). Inhibition of CD73 eliminates a major pathway of ADO production in the TME and can reverse ADO-mediated immune suppression. Extensive interrogation of structure-activity relationships (SARs), structure-based drug design, and optimization of pharmacokinetic properties culminated in the discovery of AB680, a highly potent (Ki = 5 pM), reversible, and selective inhibitor of CD73. AB680 is further characterized by very low clearance and long half-lives across preclinical species, resulting in a PK profile suitable for long-acting parenteral administration. AB680 is currently being evaluated in phase 1 clinical trials. Initial data show AB680 is well tolerated and exhibits a pharmacokinetic profile suitable for biweekly (Q2W) iv-administration in human.
- Lawson, Kenneth V.,Kalisiak, Jaroslaw,Lindsey, Erick A.,Newcomb, Eric T.,Leleti, Manmohan Reddy,Debien, Laurent,Rosen, Brandon R.,Miles, Dillon H.,Sharif, Ehesan U.,Jeffrey, Jenna L.,Tan, Joanne B. L.,Chen, Ada,Zhao, Sharon,Xu, Guifen,Fu, Lijuan,Jin, Lixia,Park, Tim W.,Berry, Wade,Moschütz, Susanne,Scaletti, Emma,Str?ter, Norbert,Walker, Nigel P.,Young, Stephen W.,Walters, Matthew J.,Schindler, Uli,Powers, Jay P.
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p. 11448 - 11468
(2020/11/26)
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- PARENTERALLY ADMINISTERED IMMUNE ENHANCING DRUGS
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Methods of identifying compounds that modulate the conversion of AMP to adenosine by 5'-nucleotidase, ecto, and that possess particular pharmacokinetic characteristics are described herein. Methods of such compounds, and compositions comprising same, for the treatment and/or prevention of a diverse array of diseases, disorders and conditions, including cancer- and immune-related disorders, are also provided.
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Paragraph 0292
(2019/10/01)
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- INHIBITORS OF ADENOSINE 5'-NUCLEOTIDASE
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Compounds that modulate the conversion of AMP to adenosine by 5'- nucleotidase, ecto, and compositions containing the compounds and methods for synthesizing the compounds, are described herein. The use of such compounds and compositions for the treatment
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Paragraph 0211
(2018/04/21)
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- INHIBITORS OF CD73-MEDIATED IMMUNOSUPPRESSION
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Compounds that modulate the conversion of AMP to adenosine by 5'- nucleotidase, ecto, and compositions containing the compounds and methods for synthesizing the compounds, are described herein. The use of such compounds and compositions for the treatment and/or prevention of a diverse array of diseases, disorders and conditions, including cancer- and immune-related disorders, that are mediated by 5'- nucleotidase, ecto is also provided.
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Paragraph 0187
(2018/06/06)
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- MODULATORS OF 5'-NUCLEOTIDASE, ECTO AND THE USE THEREOF
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Compounds that modulate the conversion of AMP to adenosine by 5'- nucleotidase, ecto, and compositions containing the compounds and methods for synthesizing the compounds, are described herein. The use of such compounds and compositions for the treatment and/or prevention of a diverse array of diseases, disorders and conditions, including cancer- and immune-related disorders, that are mediated by 5'-nucleotidase, ecto is also provided.
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Paragraph 0179
(2017/08/01)
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- METHODS OF PREVENTING, REDUCING OR TREATING MACULAR DEGENERATION
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The present invention is directed to selective adenosine A1 agonist compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat, reduce or prevent age-related macular degeneration.
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Page/Page column 45
(2016/06/28)
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- METHOD OF PROVIDING OCULAR NEUROPROTECTION
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Provided herein are compounds of Formula I, compositions comprising an effective amount of a compound of Formula I, and methods for preventing, reducing or treating retinal ganglion cell damage comprising administering an effective amount of a purine deri
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Paragraph 0177
(2014/09/30)
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- COMBINATION, KIT AND METHOD OF REDUCING INTRAOCULAR PRESSURE
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The present invention is directed to a combination or a kit comprising a prostaglandin analog and an adenosine receptor A1 agonist and to a method of reducing intraocular pressure (IOP) in a subject using such combination or kit. The invention is particularly directed to a combination of latanoprost marketed under the brand Xalatan? and Compound A.
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- METHOD OF REDUCING INTRAOCULAR PRESSURE IN HUMANS
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Provided herein are compounds of Formula I, compositions comprising an effective amount of a compound of Formula I, and methods for reducing intraocular pressure comprising administering an effective amount of compounds of Formula I to a subject in need t
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Page/Page column 35
(2010/11/17)
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- A1 ADENOSINE RECEPTOR AGONISTS
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Disclosed are novel compounds that are partial and full A1 adenosine receptor agonists having the structure of Formula (I): which are useful for treating various disease states, in particular tachycardia and atrial flutter, angina, and myocardial infarction.
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Page/Page column 36-37
(2008/06/13)
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- A1 ADENOSINE RECEPTOR AGONISTS
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Disclosed are novel compounds that are partial and foil A1 adenosine receptor agonists having the structure of Formula (I) : which are useful for treating various disease states, in particular tachycardia and atrial flutter, angina, and myocardial infarction.
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Page/Page column 38
(2010/11/25)
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- PURINE DERIVATIVES AS ADENOSINE A1 RECEPTOR AGONISTS AND METHODS OF USE THEREOF
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The invention relates to Purine Derivatives, compositions comprising an effective amount of a Purine Derivative; and methods for reducing an animal’s rate of metabolism, protecting an animal’s heart against myocardial damage during cardioplegia; or for treating or preventing a cardiovascular disease, a neurological disorder, an ischemic condition, a reperfusion injury, obesity, or wasting disease, or diabetes, comprising administering an effective amount of a Purine Derivative to an animal in need thereof.
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Page/Page column 129
(2008/06/13)
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- N-cycloalkyl derivatives of adenosine and 1-deazaadenosine as agonists and partial agonists of the A1 adenosine receptor
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A number of cycloalkyl substituents (from C-3 to C-8) have been introduced on the 6-amino group of adenosine, 1-deazaadenosine, and 2'- deoxyadenosine, bearing or not a chlorine atom at the 2-position, to evaluate the influence on the A1 and A(
- Vittori, Sauro,Lorenzen, Anna,Stannek, Christina,Costanzi, Stefano,Volpini, Rosaria,Ijzerman, Adriaan P.,Von Frijtag Drabbe Kunzel, Jakobien K.,Cristalli, Gloria
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p. 250 - 260
(2007/10/03)
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- Activity of N6-substituted 2-chloroadenosines at A1 and A2 adenosine receptors.
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Radioligand binding studies of N6-substituted adenosines at the A1 and A2 adenosine receptors of rat brain cortex and rat brain striatum, respectively, show that a 2-chloro substituent does not consistently change the affinity or the selectivity of these analogues for the A1 receptor. A 2-chloro substituent lowers the characteristic stereoselectivity of the A1 receptor toward the R diastereomer of N6-(1-phenyl-2-propyl)adenosine. A 2-chloro substituent consistently increases potency of N6-substituted adenosines as agonists at an adenosine A2 receptor stimulatory to adenylate cyclase in PC12 cell membranes.
- Thompson,Secunda,Daly,Olsson
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p. 3388 - 3390
(2007/10/02)
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