870822-98-3

Upstream product

• 172168-01-3 ethyl 3-(3,5-dichlorophenyl)-3-oxopropanoate 
• 875558-57-9 {(1S)1-[4-(ethoxycarbonyl)phenyl]ethyl}hydrazinium chloride 
• 358-23-6 trifluoromethylsulfonic anhydride 
• 1383937-87-8 tert-butyl N-(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]ethyl}benzoyl)-β-alaninate 
• 870823-08-8 ethyl 4-{(1S)1-[3-(3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]ethyl}benzoate 
• 870822-97-2 tert-butyl N-{4-[1-(3-(3,5-dichlorophenyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoyl}-β-alaninate 

Downstream Products

• 1383937-94-7 N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methylnaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine 
• 1383937-95-8 N-({4-[(1S)-1-{3-(3,5-dichlorophenyl)-5-[6-(propan-2-yl)naphthalen-2-yl]-1H-pyrazol-1-yl}ethyl]phenyl}carbonyl)-β-alanine 
• 870823-12-4 MK-0893 
• 870823-13-5 tert-butyl N-(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoyl)-β-alaninate 

Relevant academic research and scientific papers

Discovery of a novel glucagon receptor antagonist N-[(4-{(1 S)-1-[3-(3, 5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1 H -pyrazol-1-yl]ethyl}phenyl) carbonyl]-β-alanine (MK-0893) for the treatment of type II diabetes

A potent, selective glucagon receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5- dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl) carbonyl]-β-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC50 of 6.6 nM) and functional cAMP activity (IC50 of 15.7 nM). It is selective for glucagon receptor relative to other family B GPCRs, showing IC50 values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.

SUBSTITUTED PYRAZOLES, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF USE

The present invention relates to substituted pyrazoles, compositions containing such compounds and methods of treatment. The compounds are glucagon receptor antagonists and thus are useful for treating, preventing or delaying the onset of type 2 diabetes