149007-83-0Relevant articles and documents
Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors
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.
, p. 845 - 860 (2021/02/05)
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.
Discovery of AB680: A Potent and Selective Inhibitor of CD73
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.
, p. 11448 - 11468 (2020/11/26)
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.
N-cycloalkyl derivatives of adenosine and 1-deazaadenosine as agonists and partial agonists of the A1 adenosine receptor
Vittori, Sauro,Lorenzen, Anna,Stannek, Christina,Costanzi, Stefano,Volpini, Rosaria,Ijzerman, Adriaan P.,Von Frijtag Drabbe Kunzel, Jakobien K.,Cristalli, Gloria
, p. 250 - 260 (2007/10/03)
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(
C-2 functionalized N6-cyclosubstituted adenosines: Highly selective agonists for the adenosine A1 receptor
Nair, Vasu,Fasbender, Allen J.
, p. 2169 - 2184 (2007/10/02)
Synthesis of novel N6-cyclosubstituted isoguanosines and related C-2 functionalized compounds utilizing methodologies with key thermal radical and photochemical steps developed in our laboratory is described. Data on the affinities of these new
