Structure of 1614-73-9
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Lucas B. Fallot ; R. Rama Suresh ; Courtney L. Fisher ; Veronica Salmaso ; Robert D. O’Connor ; Noy Kaufman , et al.
Abstract: We previously reported 1H-imidazo[4,5-c]quinolin-4-amines as A3 adenosine receptor (A3AR) positive allosteric modulators (PAMs). A3AR agonists, but not PAMs, are in clinical trials for inflammatory diseases and liver conditions. We synthesized new analogues to distinguish 2-cyclopropyl antagonist 17 (orthosteric interaction demonstrated by binding and predicted computationally) from PAMs (derivatives with large 2-alkyl/cycloalkyl/bicycloalkyl groups). We predicted PAM binding at a hydrophobic site on the A3AR cytosolic interface. Although having low Caco-2 permeability and high plasma protein binding, hydrophobic 2-cyclohept-4-enyl-N-3,4-dichlorophenyl, MRS7788 18, and 2-heptan-4-yl-N-4-iodophenyl, MRS8054 39, derivatives were orally bioavailable in rat. 2-Heptan-4-yl-N-3,4-dichlorophenyl 14 and 2-cyclononyl-N-3,4-dichlorophenyl 20 derivatives and 39 greatly enhanced Cl-IB-MECA-stimulated [35S]GTPγS binding Emax, with only 12b trending toward decreasing the agonist EC50. A feasible route for radio-iodination at the p-position of a 4-phenylamino substituent suggests a potential radioligand for allosteric site binding. Herein, we advanced an allosteric approach to developing A3AR-activating drugs that are potentially event- and site-specific in action.
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Discovery of Allosteric Modulators of the A3 Adenosine Receptor for Treatment of Chronic Diseases
Fallot, Lucas Brett ;
Abstract: Positive allosteric modulators (PAMs) of G protein-coupled receptors (GPCRs) bind to topographically distinct sites from orthosteric agonists, causing receptor conformational changes that increase agonist affinity, potency, and/or efficacy. 1Himidazo[4,5-c]quinolin-4-amine derivatives were identified as A3 adenosine receptor (A3AR) PAMs. Here, we introduce a 6-step synthesis applied to four groups of 1Himidazo[4,5-c]quinolin-4-amine derivatives to explore structure-activity relationships and pharmacokinetics. We show the ability to fine-tune both 2-cycloalkyl and open ring derivatives as competitive antagonists and/or allosteric modulators. These activities were separated pharmacologically using chimeric mouse/human A3ARs to show the PAM binding region likely to occur at a hydrophobic site on the A3AR cytosolic interface distinct from the orthosteric site. 2-Cyclononyl-N-(3,4-dichlorophenyl) 20 (1 µM) derivative increased the A3AR agonist potency two-fold in [ 35S]GTPγS binding, as well as Emax (242%). 2-(Heptan-4-yl)-N-(3,4-dichlorophenyl) 2, 2-(hept-4-en-1-yl)-N-(3,4- viii dichlorophenyl) 10, and 2-(heptan-4-yl)-N-(4-iodophenyl) 31 (1 µM) derivatives were highly efficacious (Emax = 216%, 241% and, 223%, respectively). Although hydrophobic and having low permeability and high plasma protein binding, derivative 10 was orally bioavailable in the rat. The derivatives tested lacked high-affinity off-target binding to forty-five other membrane proteins. Furthermore, we demonstrated a route for radioiodination at the para-position of a 4-phenylamino substituent to prepare a radioligand for allosteric site binding. Herein, we advanced the allosteric approach to developing drugs for A3AR activation that are potentially event- and site-specific in action.
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CAS No. : | 1614-73-9 |
Formula : | C8H12O2 |
M.W : | 140.18 |
SMILES Code : | O=C(C1CCC=CCC1)O |
MDL No. : | MFCD00021676 |
InChI Key : | MVALBWJIVQGSGK-UHFFFAOYSA-N |
Pubchem ID : | 292754 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.62 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 39.75 |
TPSA ? Topological Polar Surface Area: Calculated from |
37.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.53 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.63 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.82 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.46 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.2 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.53 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.67 |
Solubility | 3.0 mg/ml ; 0.0214 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.03 |
Solubility | 1.32 mg/ml ; 0.00942 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.47 |
Solubility | 47.1 mg/ml ; 0.336 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.0 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.85 |
Tags: 1614-73-9 synthesis path| 1614-73-9 SDS| 1614-73-9 COA| 1614-73-9 purity| 1614-73-9 application| 1614-73-9 NMR| 1614-73-9 COA| 1614-73-9 structure
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