Merck + Co., Inc.

Stephan K Grant

Malcolm MacCoss

Philippe L Durette

Shrenik K Shah

Charles G Caldwell

Ravindra N Guthikonda

Gregory J Kaczorowski

Kothandaraman Shankaran

Richard E Middleton

The present invention provides assays in which intracellular chelators are used to alter the kinetics of signal generation triggered by divalent cations, particularly calcium influx into the cell. The use of an intracellular chelator in the assay can delay and prolong the signal, allowing the signal to be detected by automated instrumentation without the need for simultaneous liquid handling at the time of detection.

High throughput screening by measurement of intracellular calcium levels

Disclosed herein are compounds of Formula I ##STR1## and pharmaceutically acceptable salts thereof which have been found useful in the treatment of nitric oxide synthase mediated diseases and disorders, including neurodegenerative disorders, disorders of gastrointestinal motility and inflammation. These disease and disorders include hypotension, septic shock, toxic shock syndrom, hemodialysis, IL-2 therapy such as in cancer patients, cachexia, immunosuppression such as in transplant therapy, autoimmune and/or inflammatory indications including sunburn or psoriasis and respiratory conditions such as bronchitis, asthma, and acure respiratory distress (ARDS), myocarditis, heart failure, atherosclerosis, arthritis, rheumatoid arthritis, chronic or inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosis (SLE), ocular conditions such as ocular hypertension and uveitis, type 1 diabetes, insulin-dependent diabetes mellitus and cystic fibrosis. Compounds of Formula I are also usful in the treatment of hypoxia, hyperbaric oxygen convulsions and toxicity, dementia, Sydenham's chorea, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, mulitple sclerosis, Korsakoff's disease, imbecility related to cerebral vessel disorder, ischemic brain edema, sleeping disorders, schizophrenia, depression, PMS, anxiety, drug addiction, pain, migraine, immune complex disease, as immunosupressive agents and for preventing or reversing tolerance to opiates and diazepines.

Cyclic amidine analogs as inhibitors of nitric oxide synthase

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East Windsor, NJ, United States of America

Stephan K Grant