101724-61-2Relevant articles and documents
NOVEL STING AGONISTS
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, (2020/05/14)
The present invention provides compounds of Formula I′: wherein , W, X, Y, Z, Z1, Z2, R1, R2, R3, R4 and R5 are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug ester or solvate form thereof, wherein all of the variables are as defined herein. These compounds are effective at modulating the STING protein and thus can be used as medicaments for treating or preventing disorders affected by the agonism of STING.
Preparation of an advanced intermediate for the synthesis of stable analogues of guanofosfocin
George, Tesmol G.,Szolcsanyi, Peter,Koenig, Stefan G.,Paterson, Duncan E.,Isshiki, Yoshiaki,Vasella, Andrea
, p. 1287 - 1298 (2007/10/03)
The synthesis of C-mannosyl-guanosine 23, an advanced intermediate for the preparation of stable analogues of guanofosfocin, is described. This convergent approach features an improved Traube-type synthesis of a 8-substituted guanine, followed by ribosylation. NMR Studies show that the C-mannopyranosyl moiety of 23 adopts a distorted 1C4 conformation while the nucleoside is predominantly syn-oriented.
4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2.
Mesguiche, Veronique,Parsons, Rachel J,Arris, Christine E,Bentley, Johanne,Boyle, F Thomas,Curtin, Nicola J,Davies, Thomas G,Endicott, Jane A,Gibson, Ashleigh E,Golding, Bernard T,Griffin, Roger J,Jewsbury, Philip,Johnson, Louise N,Newell, David R,Noble, Martin E M,Wang, Lan Z,Hardcastle, Ian R
, p. 217 - 222 (2007/10/03)
The cyclin dependent kinase (cdk) inhibitor NU6027, 4-cyclohexylmethoxy-5-nitroso-pyrimidine-2,6-diamine (IC(50) vs cdk1/cyclinB1=2.9+/-0.1 microM and IC(50) vs cdk2/cyclinA3=2.2+/-0.6 microM), was used as the basis for the design of a series of 4-alkoxy-2,6-diamino-5-nitrosopyrimidine derivatives. The synthesis and evaluation of 21 compounds as potential inhibitors of cyclin-dependent kinases 1 and 2 is described and the structure-activity relationships relating to NU6027 have been probed. Simple alkoxy- or cycloalkoxy-groups at the O(4)-position were tolerated, with the 4-(2-methylbutoxy)-derivative (IC(50) vs cdk1/cyclinB1=12+/-2 microM and cdk2/cyclinA3=13+/-4 microM) retaining significant activity. Substitutions at the N(6) position were not tolerated. Replacement of the 5-nitroso substituent with ketone, oxime and semicarbazone groups essentially abolished activity. However, the derivative bearing an isosteric 5-formyl group, 2,6-diamino-4-cyclohexylmethoxy-pyrimidine-5-carbaldehyde, showed modest activity (IC(50) vs cdk1/cyclinB1=35+/-3 microM and cdk2/cyclinA3=43+/-3 microM). The X-ray crystal structure of the 5-formyl compound bound to cdk2 has been determined to 2.3A resolution. The intramolecular H-bond deduced from the structure with NU6027 bound to cdk2 is not evident in the structure with the corresponding formyl compound. Thus the parent compound, 4-cyclohexylmethoxy-5-nitrosopyrimidine-2,6-diamine (NU6027), remains the optimal basis for future structure-activity studies for cyclin-dependent kinase inhibitors in this series.
