15001-13-5

Upstream product

• 42466-67-1 ethyl (ethoxymethylene)cyanoacetate 
• 3471-32-7 4-Methoxyphenylhydrazine 
• 94-05-3 ethyl (ethoxymethylene)cyanoacetate 
• 19501-58-7 4-methoxyphenylhydrazine hydrochloride 
• 144918-37-6 (E)-ethyl 2-cyano-3-ethoxyacrylate 
• 94-05-3 2-cyano-3-ethoxyacrylic acid ethyl ester 

Downstream Products

• 110821-34-6 ethyl 1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylate 
• 98534-72-6 5-chloro-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester 
• 203123-04-0 C₁₅H₁₉N₃O₇S₂ 
• 16907-09-8 2-(4-methoxyphenyl)-2H-pyrazol-3-ylamine 
• 1235035-27-4 1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(3aH)-one 
• 1200439-60-6 2-[1-(2,5-dimethyl-phenyl)-1H-tetrazol-5-ylsulfanyl]-N-[2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-acetamide 
• 1044140-04-6 ethyl 5-(3-benzoylthioureido)-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylate 
• 14678-95-6 5-amino-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid 
• 1235035-61-6 4-(4-(3-(dimethylamino)propylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenol 

Relevant academic research and scientific papers

Synthesis, crystal structure, magnetic properties and DFT calculations of a mononuclear copper(II) complex: Relevance of halogen bonding for magnetic interaction

The synthesis, crystal structure, magnetic properties and DFT calculations of a new mononuclear copper(II) complex containing a pyrazole-based ligand are reported. In the crystal structure of the [CuCl2L2] complex (L = Ethyl 5-amino-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylate), a network of hydrogen bonds connects the molecular units in the crystal packing. The magnetic studies revealed predominant antiferromagnetic interactions among molecular units. Since there are multiple intermolecular contacts that can act as pathway for magnetic interactions, DFT calculations revealed the fundamental role of N–H?Cl short intermolecular contacts in magnetic behavior. Supported by DFT calculation, the magnetic data above 7.0 K was modeled as a regular Heisenberg chain (H=-2J∑i=1n-1S→Ai·S→Ai+1) resulting in a weak magnetic coupling constant (J) of ?2.6 cm?1. Below this temperature, an unusual magnetic behavior for mononuclear copper(II) complexes was observed: divergence between zero-field cooled (ZFC) and field cooled (FC) magnetic susceptibilities and magnetic hysteresis cycles at low temperatures attributed to spin canting along the chain.

Design, synthesis and biological evaluation of novel pyrazolo-pyrimidinones as DPP-IV inhibitors in diabetes

We report the design, synthesis, biological activity and docking studies of series of novel pyrazolo[3,4-d]pyrimidinones as DPP-IV inhibitors in diabetes. Molecules were synthesized and evaluated for their DPP-IV inhibition activity. Compounds 5e, 5k, 5o and 6a were found to be potent inhibitors of DPP-IV enzyme. Amongst all the synthesized compounds, 6-methyl-5-(4-methylpyridin-2-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (5k) was found to be the most active based on in vitro DPP-IV studies and also exhibited promising in vivo blood glucose lowering activity in male Wistar rats.

The optimization and characterization of functionalized sulfonamides derived from sulfaphenazole against Mycobacterium tuberculosis with reduced CYP 2C9 inhibition

In this study, a series of sulfonamide compounds was designed and synthesized through the systematic optimization of the antibacterial agent sulfaphenazole for the treatment of Mycobacterium tuberculosis (M. tuberculosis). Preliminary results indicate that the 4-aminobenzenesulfonamide moiety plays a key role in maintaining antimycobacterial activity. Compounds 10c, 10d, 10f and 10i through the optimization on phenyl ring at the R2 site on the pyrazole displayed promising antimycobacterial activity paired with low cytotoxicity. In particular, compound 10d displayed good activity (MIC = 5.69 μg/mL) with low inhibition of CYP 2C9 (IC50 > 10 μM), consequently low potential risk of drug-drug interaction. These promising results provide new insight into the combination regimen using sulfonamide as one component for the treatment of M. tuberculosis.

Synthesis of pyrazole-carboxamides and pyrazole-carboxylic acids derivatives: Simple methods to access powerful building blocks

Hybrid systems containing pyrazole moiety show a wide spectrum of biological activities. To access novel hybrids with pyrazole ring, in this work we synthesized twenty pyrazole-carboxylic acids and twenty pyrazole-carboxamides, using simple synthetic methods, to be used as building blocks in the development of new structures.

Targeting Pim Kinases and DAPK3 to Control Hypertension

Sustained vascular smooth muscle hypercontractility promotes hypertension and cardiovascular disease. The etiology of hypercontractility is not completely understood. New therapeutic targets remain vitally important for drug discovery. Here we report that Pim kinases, in combination with DAPK3, regulate contractility and control hypertension. Using a co-crystal structure of lead molecule (HS38) in complex with DAPK3, a dual Pim/DAPK3 inhibitor (HS56) and selective DAPK3 inhibitors (HS94 and HS148) were developed to provide mechanistic insight into the polypharmacology of hypertension. In vitro and ex vivo studies indicated that Pim kinases directly phosphorylate smooth muscle targets and that Pim/DAPK3 inhibition, unlike selective DAPK3 inhibition, significantly reduces contractility. In vivo, HS56 decreased blood pressure in spontaneously hypertensive mice in a dose-dependent manner without affecting heart rate. These findings suggest including Pim kinase inhibition within a multi-target engagement strategy for hypertension management. HS56 represents a significant step in the development of molecularly targeted antihypertensive medications. Carlson et al. use crystal structure-guided medicinal chemistry techniques to develop a dual Pim/DAPK3 inhibitor (HS56) that reduces myosin phosphorylation and contractility in smooth muscle. Their findings reveal the contribution of Pim kinases to the pathology of hypertension, suggesting a novel multi-target engagement strategy for molecularly targeted antihypertensive medications.

A novel solid-phase synthetic method for production of N-alkyl-4-alkylamino-1-aryl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide library

This work describes a solid-phase synthetic method for building a compound library of N-alkyl-4-alkylamino-1-aryl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide derivatives, that are based on the biologically active 1-aryl-1H-pyrazolo[3,4-d]pyrimidine scaffold. In the first step of this synthetic sequence, condensation reactions of ethyl 5-amino-1-aryl-1H-pyrazole-4-carboxylates with methyl cyanoformate resulted in the formation of esters that underwent hydrolysis to give 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one-6-carboxylic acids. The coupling reaction of these carboxylic acids with primary alkylamine-loaded acid-sensitive methoxybenzaldehyde (AMEBA) resins was followed by amination reactions mediated by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP). Subsequent cleavage from the solid support resulted in the formation of the target N-alkyl-4-alkylamino-1-aryl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide derivatives. The reaction conditions for solid-phase transformations were optimized using a solution-phase model study with 2,4-dimethoxybenzyl-protected isobutylamine as a reactant in place of the AMEBA resin-loaded isobutylamine. The progress of the solid-phase reactions was monitored by on-bead ATR-FTIR spectroscopy. Diversification experiments were performed by using 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one-6-carboxylic acids and a variety of primary and secondary amine building blocks to build the target compound library.

A Michael Equilibration Model to Control Site Selectivity in the Condensation toward Aminopyrazoles

A Michael equilibration model is presented to provide for site-selective pyrazole condensations between alkoxyacrylonitriles and hydrazines. Both pyrazole isomers were accessed with high selectivity by employment of kinetically or thermodynamically controlled conditions. Substrate scope and identification of Michael intermediates, as well as competitive pathways, support the presented mechanistic proposal. Sandmeyer derivatization provided site-selective access to fully substituted pyrazoles.

Discovery of a potent and selective BCL-XLinhibitor with in vivo activity

A-1155463, a highly potent and selective BCL-XLinhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XLbiology as well as a productive lead structure for further optimization.

PYRAZOLOPYRIDINES USEFUL IN THE TREATMENT OF DISORDERS OF THE CENTRAL NERVOUS SYSTEM

The present invention relates to compounds useful in therapy, to compositions comprising said compounds, and to methods of treating diseases comprising administration of said com- pounds. The compounds referred to are positive allosteric modulators (PAMs) of the nicotinic acetylcholine α7 receptor.

NEW POSITIVE ALLOSTERIC MODULATORS OF NICOTINIC ACETYLCHOLINE RECEPTOR

The present invention relates to compounds useful in therapy, to compositions comprising said compounds, and to methods of treating diseases comprising administration of said compounds. The compounds referred to are positive allosteric modulators (PAMs) of the nicotinic acetylcholine alpha7 receptor.