221243-82-9

Usage

Chemical Properties

White Cyrstalline Solid

Biological Activity

Selective inhibitor of src family kinases v-Src and c-Fyn as well as the tyrosine kinase c-Abl. (IC 50 values are 1.0, 0.6, 0.6, 18 and 22 μ M for v-Src, c-Fyn, c-Abl, CDK2 and CAMK II respectively). Preferentially inhibits mutant over wild-type kinases (IC 50 values are 1.5 vs 1000 nM for I338G v-src and v-src respectively).

Synthesis

Add 3-iodo-1-tert-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine into a 250mL three-necked flask, dissolve in 300ml 10% Na2CO3, add 150ml dioxane, After cooling to 0 °C, Fmoc boronate was dissolved in 225 ml of acetone and added dropwise to the system. Stir at room temperature for 3h, pour into 1000ml of water, extract twice with ether, cool and adjust pH to about 2 with concentrated hydrochloric acid, extract with ethyl acetate (3×100ml), dry over MgSO4, evaporate the solvent, and rotate under reduced pressure. The crude product is subjected to silica gel column chromatography (V methanol: V dichloromethane=1:35) to give 4-amino-1-tert-butyl-3-(1'-naphthyl)pyrazolo[3,4-D] pyrimidine as a white crystal-like solid .

InChI:InChI=1/C19H19N5/c1-19(2,3)24-18-15(17(20)21-11-22-18)16(23-24)14-10-6-8-12-7-4-5-9-13(12)14/h4-11H,1-3H3,(H2,20,21,22)

Upstream product

• 77287-34-4 formamide 
• 221243-34-1 5-amino-1-tert-butyl-3-naphthalen-1-yl-1H-pyrazole-4-carbonitrile 
• 879-18-5 naphthalene-1-carbonic acid chloride 
• 7400-27-3 tertbutylhydrazine hydrochloride 
• 1236038-48-4 C₁₄H₈N₂O 
• 862728-60-7 1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 
• 158001-28-6 5-amino-1-(tert-butyl)-1H-pyrazole-4-carbonitrile 
• 862728-61-8 3-bromo-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 
• 13922-41-3 1-Naphthylboronic acid 
• 86-55-5 1-naphthalenecarboxylic acid 
• 221242-71-3 2-(methoxy-naphthalen-1-yl-methylene)-malononitrile 

Relevant academic research and scientific papers

Discovery of a potent protein kinase D inhibitor: insights in the binding mode of pyrazolo[3,4-d]pyrimidine analogues

In this study, we set out to rationally optimize PKD inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold. The lead compound for this study was 1-NM-PP1, which was previously found by us and others to inhibit PKD. In our screening we identified one compound (3-IN-PP1) displaying a 10-fold increase in potency over 1-NM-PP1, opening new possibilities for specific protein kinase inhibitors for kinases that show sensitivity towards pyrazolo[3,4-d]pyrimidine derived compounds. Interestingly the observed SAR was not in complete agreement with the commonly observed binding mode where the pyrazolo[3,4-d]pyrimidine compounds are bound in a similar fashion as PKD's natural ligand ATP. Therefore we suggest an alternate binding mode where the compounds are flipped 180 degrees. This possible alternate binding mode for pyrazolo[3,4-d]pyrimidine based compounds could pave the way for a new class of specific protein kinase inhibitors for kinases sensitive towards pyrazolo[3,4-d]pyrmidines.

1,3-disubstituted-4-aminopyrazolo [3, 4-d] pyrimidines, a new class of potent inhibitors for phospholipase D

Phospholipase D enzymes cleave lipid substrates to produce phosphatidic acid, an important precursor for many essential cellular molecules. Phospholipase D is a target to modulate cancer-cell invasiveness. This study reports synthesis of a new class of phospholipase D inhibitors based on 1,3-disubstituted-4-amino-pyrazolopyrimidine core structure. These molecules were synthesized and used to perform initial screening for the inhibition of purified bacterial phospholipase D, which is highly homologous to the human PLD1. Initially tested with the bacterial phospholipase D enzyme, then confirmed with the recombinant human PLD1 and PLD2 enzymes, the molecules presented here exhibited inhibition of phospholipase D activity (IC50) in the low-nanomolar to low-micromolar range with both monomeric substrate diC4PC and phospholipid vesicles and micelles. The data strongly indicate that these inhibitory molecules directly block enzyme/vesicle substrate binding. Preliminary activity studies using recombinant human phospholipase Ds in in vivo cell assays measuring both transphosphatidylation and head-group cleavage indicate inhibition in the mid- to low-nanomolar range for these potent inhibitory novel molecules in a physiological environment. This study reports synthesis of a new class of PLD inhibitors based on 1,3-disubstituted-4-amino-pyrazolopyrimidine core structure. These molecules exhibited inhibition of human recombinant PLD activity (IC 50) in the low-nanomolar to low-micromolar range with monomeric substrate diC4PC and phospholipid vesicles and micelles. Preliminary activity studies using recombinant human PLDs in in vivo cell assays measuring both transphosphatidylation and head-group cleavage indicates inhibition in the mid- to low-nanomolar range for these potent inhibitory novel molecules in a physiological environment.

Optimizing small molecule inhibitors of calcium-dependent protein kinase 1 to prevent infection by toxoplasma gondii

Toxoplasma gondii is sensitive to bulky pyrazolo [3,4-d] pyrimidine (PP) inhibitors due to the presence of a Gly gatekeeper in the essential calcium dependent protein kinase 1 (CDPK1). Here we synthesized a number of new derivatives of 3-methyl-benzyl-PP (3-MB-PP, or 1). The potency of PP analogues in inhibiting CDPK1 enzyme activity in vitro (low nM IC50 values) and blocking parasite growth in host cell monolayers in vivo (low μM EC 50 values) were highly correlated and occurred in a CDPK1-specific manner. Chemical modification of the PP scaffold to increase half-life in the presence of microsomes in vitro led to identification of compounds with enhanced stability while retaining activity. Several of these more potent compounds were able to prevent lethal infection with T. gondii in the mouse model. Collectively, the strategies outlined here provide a route for development of more effective compounds for treatment of toxoplasmosis and perhaps related parasitic diseases.

COMPOSITIONS AND METHODS FOR TREATING TOXOPLASMOSIS. CRYPTOSPORIDIOSIS AND OTHER APICOMPLEXAN PROTOZOAN RELATED DISEASES

Compositions and methods for the treatment of toxoplasmosis-, caused by the infectious eukaryotic parasite Toxoplasma gondii (T, gondii) and for the treatment of ciyptosporidiosis, caused by the infectious eukaryotic parasites Cryptosporidium parvum (C parvuai) and Cnγtosporidium homimus (C. hominus) are described. In particular, the present disclosure is directed to compositions and methods for inhibiting either T. gondii calcium dependent protein kinases (TgCDPKs) or C. parvum and C. hominus calcium dependent protein kinases (CpDPKS) using pyrazolopyriinidine and/or imidazo[l,5-a]pyraziαe inhibitors, of the formula.(I), wherein the variables X. Y, Z, L. R1. and R3 are defined herein.

MODULATION OF PROTEIN TRAFFICKING

Compounds and compositions are provided for treatment or amelioration of one or more disorders characterized by defects in protein trafficking. A method of treating a disorder characterized by impaired protein trafficking includes administering to a subject or contacting a cell with a compound of Formula I: [formula here] or pharmaceutically acceptable salts or derivatives thereof.

Generation of monospecific nanomolar tyrosine kinase inhibitors via a chemical genetic approach

Selective protein kinase inhibitors are highly sought after as tools for studying cellular signal transduction cascades, yet few have been discovered due to the highly conserved fold of kinase catalytic domains. Through a combination of small molecule syn