793695-59-7Relevant articles and documents
COMPOUNDS TARGETING PRMT5
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, (2021/10/11)
Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
COMPOUNDS TARGETING PRMT5
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, (2020/10/20)
Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
South (S)- and north (N)-methanocarba-7-deazaadenosine analogues as inhibitors of human adenosine kinase
Toti, Kiran S.,Osborne, Danielle,Ciancetta, Antonella,Boison, Detlev,Jacobson, Kenneth A.
supporting information, p. 6860 - 6877 (2016/08/05)
Adenosine kinase (AdK) inhibitors raise endogenous adenosine levels, particularly in disease states, and have potential for treatment of seizures, neurodegeneration, and inflammation. On the basis of the South (S) ribose conformation and molecular dynamics (MD) analysis of nucleoside inhibitors bound in AdK X-ray crystallographic structures, (S)- and North (N)-methanocarba (bicyclo[3.1.0]hexane) derivatives of known inhibitors were prepared and compared as human (h) AdK inhibitors. 5′-Hydroxy (34, MRS4202 (S); 55, MRS4380 (N)) and 5′-deoxy 38a (MRS4203 (S)) analogues, containing 7- and N6-NH phenyl groups in 7-deazaadenine, robustly inhibited AdK activity (IC50 ～ 100 nM), while the 5′-hydroxy derivative 30 lacking the phenyl substituents was weak. Docking in the hAdK X-ray structure and MD simulation suggested a mode of binding similar to 5′-deoxy-5-iodotubercidin and other known inhibitors. Thus, a structure-based design approach for further potency enhancement is possible. The potent AdK inhibitors in this study are ready to be further tested in animal models of epilepsy.
Structure-activity relationship of (N)-methanocarba phosphonate analogues of 5′-AMP as cardioprotective agents acting through a cardiac P2X receptor
Santhosh Kumar,Zhou, Si-Yuan,Joshi, Bhalchandra V.,Balasubramanian, Ramachandran,Yang, Tiehong,Liang, Bruce T.,Jacobson, Kenneth A.
supporting information; experimental part, p. 2562 - 2576 (2010/08/19)
P2X receptor activation protects in heart failure models. MRS2339 3, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system, activates this cardioprotective channel. Michaelis-Arbuzov and Wittig reactions provided phosphonate analogues of 3, expected to be stable in vivo due to the C-P bond. After chronic administration via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in calsequestrin-overexpressing mice (genetic model of heart failure) compared to vehicle-infused mice (all inactive at the vasodilatory P2Y1 receptor). Two phosphonates,(1′S,2′R,3′S,4′R,5′S)- 4′-(6-amino-2-chloropurin-9-yl)-2′,3′-(dihydroxy) -1′-(phosphonomethylene)-bicyclo[3.1.0]hexane, 4 (MRS2775), and its homologue 9 (MRS2935), both 5′-saturated, containing a 2-Cl substitution, improved echocardiography-derived fractional shortening (20.25% and 19.26%, respectively, versus 13.78% in controls), while unsaturated 5′-extended phosphonates, all 2-H analogues, and a CH3-phosphonate were inactive. Thus, chronic administration of nucleotidase-resistant phosphonates conferred a beneficial effect, likely via cardiac P2X receptor activation. Thus, we have greatly expanded the range of carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure.
Synthesis of ethyl (1S,2R,3S,4S,5S)-2,3-O-(isopropylidene)-4-hydroxy- bicyclo[3.1.0]hexane-carboxylate from l-ribose: A versatile chiral synthon for preparation of adenosine and P2 receptor ligands
Joshi, Bhalchandra V.,Melman, Artem,Mackman, Richard L.,Jacobson, Kenneth A.
, p. 279 - 291 (2008/09/18)
Substitution of the ribose moiety of various nucleosides and nucleotides with the (N)-methanocarba ring system increases the potency and selectivity as ligands at certain subtypes of adenosine and P2 receptors. We have prepared a key intermediate in the synthesis of these derivatives, ethyl (1S,2R,3S,4S,5S)-2,3-O-(isopropylidene)-4-hydroxybicyclo[3.1.0] hexane-carboxylate (15), starting from L-ribose (8) as a readily available, enantiopure building block. L-ribose was converted to the corresponding 5′-iodo derivative (9), which was cleaved reductively with Zn. Improvements were made in subsequent steps corresponding to a published route to biologically important (N)-methanocarba 5′-uronamido nucleosides, and new steps were added to prepare related 5′-nucleotides. Copyright Taylor & Francis Group, LLC.
PURINE DERIVATIVES AS A3 AND A1 ADENOSINE RECEPTOR AGONISTS
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Page/Page column 22, (2010/10/20)
Disclosed are (N)-methanocarba adenine nucleosides of the formula: [Formula] as highly potent A3 adenosine receptor agonists, pharmaceutical compositions comprising such nucleosides, and a method of use of these nucleosides, wherein R1-R6 are as defined in the specification. These nucleosides are contemplated for use in the treatment a number of diseases, for example, inflammation, cardiac ischemia, stroke, asthma, diabetes, and cardiac arrhythmias. The invention also provides compounds that are agonists of both A1 and A3 adenosine receptors for use in cardioprotection.
BICYCLO (3.1.0) HEXANE DERIVATIVES AS ANTIVIRAL COMPOUNDS
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Page/Page column 43; 46, (2010/11/23)
The invention provides a compound of formula (I) and (II), or a salt or prodrug thereof, as described herein, as well as pharmaceutical compositions comprising the compounds, and therapeutic methods comprising administering the compounds. The compounds have anti-viral properties and are useful for treating viral infections (e.g. HCV) in animals (e.g. humans).
A new synthetic route to (North)-methanocarba nucleosides designed as A3 adenosine receptor agonists
Joshi, Bhalchandra V.,Hyung, Ryong Moon,Fettinger, James C.,Marquez, Victor E.,Jacobson, Kenneth A.
, p. 439 - 447 (2007/10/03)
(Chemical Equation Presented) Activation of the A3 adenosine receptor (AR) is associated with cerebroprotective, cardioprotective, and anticancer effects. Among potent and selective A3 AR agonists are novel methanocarba adenosine analogues in which the conformation of a pseudo-ribose moiety is locked in the North (N) hemisphere of the pseudorotational cycle. 5′-Uronamide (N)-methanocarba nucleosides, such as MRS1898 and MRS2346, are examples of full agonists of the human A3 AR. An improved convergent approach from easily accessible 2,3-O-isopropylidene- D-erythrose (2b), and the combination of a strategic intramolecular cyclopropanation step plus the acid-catalyzed isomerization of an isopropylidene group, provided a suitable pseudosugar precursor (23) for the synthesis of MRS1898, MRS2346, and related analogues. This new synthetic route uses readily available building blocks and opens the way for the preparation of a variety of targets on a reasonable scale.
