78682-33-4

Upstream product

• 140-53-4 p-chlorobenzyl cyanide 
• 64399-27-5 1-(4-chlorophenyl)-1-cyclopropanecarbonitrile 
• 72934-37-3 3-(4-chlorophenyl)-1-cyclopropanecarboxylic acid 

Downstream Products

• 872421-40-4 1-(4-Chlorophenyl)-N-(3-phenylpropyl)cyclopropanecarboxamide 
• 916923-29-0 1-(4-chlorophenyl)-N-[2-(4-methoxyphenyl)ethyl]cyclopropanecarboxamide 
• 633701-51-6 1-(4-chlorophenyl)-N-methylcyclopropanecarboxamide 
• 1233336-24-7 [[1-(4-chlorophenyl)cyclopropanecarbonyl]amino]thiourea 
• 1067187-87-4 1-(1-(4-chlorophenyl)cyclopropyl)-2-hydroxyethanone 
• 1309195-49-0 1-(1-(4-chlorophenyl)cyclopropyl)-2-diazoethanone 
• 1309192-24-2 2-[1-(4-chlorophenyl)cyclopropyl]-N-[1-oxo-4-(trifluoromethyl)phthalazin-2(1H)-yl]acetamide 
• 1346641-11-9 1-(4-chlorophenyl)-N-(4-cyano-2,3,5,6-tetrafluorophenyl)cyclopropanecarboxamide 
• 1083168-51-7 1-(4-chlorophenyl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide 
• 1309358-77-7 1-(4-chlorophenyl)-N-[2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenyl]cyclopropanecarboxamide 
• 1187622-03-2 Methyl 6-[3-endo-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)-8-azabicyclo[3.2.1]oct-8-yl]pyridine-3-carboxylate 
• 1187626-98-7 ethyl 3-endo-(1-(4-chlorophenyl)cyclopropane-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate 
• 78682-34-5 5-carbamoyl-1H-imidazole-4-yl 1'-(p-chlorophenyl)cyclopropane-1'-carboxylate 

Relevant academic research and scientific papers

Phenotypic Optimization of Urea-Thiophene Carboxamides to Yield Potent, Well Tolerated, and Orally Active Protective Agents against Aminoglycoside-Induced Hearing Loss

Hearing loss is a major public health concern with no pharmaceutical intervention for hearing protection or restoration. Using zebrafish neuromast hair cells, a robust model for mammalian auditory and vestibular hair cells, we identified a urea-thiophene carboxamide, 1 (ORC-001), as protective against aminoglycoside antibiotic (AGA)-induced hair cell death. The 50% protection (HC50) concentration conferred by 1 is 3.2 μM with protection against 200 μM neomycin approaching 100%. Compound 1 was sufficiently safe and drug-like to validate otoprotection in an in vivo rat hearing loss model. We explored the structure-activity relationship (SAR) of this compound series to improve otoprotective potency, improve pharmacokinetic properties and eliminate off-target activity. We present the optimization of 1 to yield 90 (ORC-13661). Compound 90 protects mechanosensory hair cells with HC50 of 120 nM and demonstrates 100% protection in the zebrafish assay and superior physiochemical, pharmacokinetic, and toxicologic properties, as well as complete in vivo protection in rats.

Chemical structure-guided design of dynapyrazoles, cell-permeable dynein inhibitors with a unique mode of action

Cytoplasmic dyneins are motor proteins in the AAA+ superfamily that transport cellular cargos toward microtubule minus-ends. Recently, ciliobrevins were reported as selective cell-permeable inhibitors of cytoplasmic dyneins. As is often true for first-in-

Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones

A series of 1,3,4-oxadiazol-2-ones was synthesized and tested for activity as antagonists at GPR55 in cellular beta-arrestin redistribution assays. The synthesis was designed to be modular in nature so that a sufficient number of analogues could be rapidly accessed to explore initial structure–activity relationships. The design of analogues was guided by the docking of potential compounds into a model of the inactive form of GPR55. The results of the assays were used to learn more about the binding pocket of GPR55. With this oxadiazolone scaffold, it was determined that modification of the aryl group adjacent to the oxadiazolone ring was often detrimental and that the distal cyclopropane was beneficial for activity. These results will guide further exploration of this receptor.

Pd(II)-catalyzed enantioselective C-H activation of cyclopropanes

Systematic ligand development has led to the identification of novel mono-N-protected amino acid ligands for Pd(II)-catalyzed enantioselective C-H activation of cyclopropanes. A diverse range of organoboron reagents can be used as coupling partners, and the reaction proceeds under mild conditions. These results provide a new retrosynthetic disconnection for the construction of enantioenriched cis-substituted cyclopropanecarboxylic acids.

Systematic investigation of halogen bonding in protein-ligand interactions

Halogen bonding triggers activity: Increasing binding affinity was observed for a series of covalent human Cathepsin L inhibitors by exchanging an aryl ring H atom with Cl, Br, and I, which undergo halogen bonding with the C=O group of Gly61 in the S3 pocket of the enzyme. Fluorine, in contrast, strongly avoids halogen bonding (see scheme). The strong distance and angle dependence of halogen bonding was confirmed for biological systems. Copyright

POTASSIUM CHANNEL MODULATORS

Disclosed herein are KCNQ potassium channels modulators of formula (I) wherein ring Z1, R1, p, R3, and R4 are as defined in the specification. Compositions comprising such compounds; and methods for treating conditions and disorders using such compounds and compositions are also described.

COMPOUNDS USEFUL AS MEDICAMENTS

There is provided a compound of formula (I), wherein the dotted lines, X, T, G, Y, A1 to A5 and D1 to D5 have meanings given in the description, which compounds are useful in the treatment of conditions or disor

Discovery of 2-[1-(4-Chlorophenyl)cyclopropyl]-3-hydroxy-8- (trifluoromethyl)quinoline-4-carboxylic acid (PSI-421), a P-selectin inhibitor with improved pharmacokinetic properties and oral efficacy in models of vascular injury

Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicylic acid-based P-selectin inhibitor. It is active in a variety of animal models of cardiovascular disease. Compound 1a has also been shown to be well tolerated and safe in healthy volunteers at doses of up to 1200 mg in a phase 1 single ascending dose study. However, its oral bioavailability was low. Our goal was to identify a back up compound with equal potency, increased solubility, and increased exposure. We expanded our structure-activity studies in this series by branching at the α position of the C-2 benzyl side chain and through modification of substituents on the carboxylic A-ring of the quinoline. This resulted in discovery of PSI-421 with marked improvement in aqueous solubility and pharmacokinetic properties. This compound has shown oral efficacy in animal models of arterial and venous injury and was selected as a preclinical development compound for potential treatment of such diseases as atherosclerosis and deep vein thrombosis.

11 Beta-HSD1 Modulators

A compound according to Formula A: or a pharmaceutically acceptable salt thereof, wherein R11, G1 and G2 are as defined in the specification, pharmaceutical compositions thereof, and methods of use thereof.

MODULATORS OF CFTR

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette ("ABC") transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator ("CFTR"). The present invention also relates to methods of treating CFTR mediated diseases using compounds of the present invention.