Synthesis and SAR of 4-carboxy-2-azetidinone mechanism-based tryptase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 12, Issue 21, 2002, Pages 3229-3233

  Sutton, James C ^a   Bolton, Scott A ^a   Hartl, Karen S ^a   Huang, Ming Hsing ^a   Jacobs, Glenn ^a   Meng, Wei ^a   Ogletree, Martin L ^a   Pi, Zulan ^a   Schumacher, William A ^a   Seiler, Steven M ^a   Slusarchyk, William A ^a   Treuner, Uwe ^a   Zahler, Robert ^a   Zhao, Guohua ^a   Bisacchi, Gregory S ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALLERGEN; BMS 262084; OVALBUMIN; SERINE PROTEINASE; TRYPTASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL MODEL; ARTICLE; BRONCHOSPASM; CELL INFILTRATION; CONTROLLED STUDY; DOSE RESPONSE; DRUG ACTIVITY; DRUG POTENCY; DRUG SPECIFICITY; DRUG SYNTHESIS; ENZYME INHIBITION; GUINEA PIG; IC 50; INFLAMMATORY CELL; ISOMER; NONHUMAN; PNEUMONIA; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTI-ASTHMATIC AGENTS; ASTHMA; AZETIDINES; BRONCHOCONSTRICTION; CRYSTALLOGRAPHY, X-RAY; EXTRACELLULAR SPACE; GUINEA PIGS; HALF-LIFE; HUMANS; INFLAMMATION; LUNG; MOLECULAR CONFORMATION; OVALBUMIN; PIPERAZINES; SERINE ENDOPEPTIDASES; SERINE PROTEINASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP; TRYPTASES;

CAVIA;

EID: 0037020747     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(02)00688-1     Document Type: Article

References (10)

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9. dyn). Ten min prior to ovalbumin challenge (50 μg/kg, iv) animals were disconnected from the ventilator and 50 μL of BMS-262084 (dose range 2.5-75 μg/kg) was administered as an aerosol intratracheal spray using a Model 1A needle (PenCentury, Philadelphia, PA) producing 25 μm median particle diameter. The trachea was reconnected to the ventilator and changes in pulmonary mechanics were followed over time.
10. In this experiment ovalbumin-sensitized guinea pigs were anesthetized with isoflurane and the trachea was exposed by a small skin incision. The Model 1A PenCentury spray injector was advanced through a small cut between adjacent tracheal rings up to the bronchial bifurcation. Saline or BMS-262084 (50 μL at 75 or 225 mg/kg) was administered as a spray and the tracheal incision was closed immediately. Ovalbumin (50 μg/kg) was injected into the jugular vein∼6 min after intratracheal dosing. The skin incision was then closed, anesthesia discontinued and the animals allowed to recover. Twenty-four h later, the guinea pigs were anesthetized with pentobarbital and subjected to bronchoaveolar lavage (BAL). Differential cell counts and protein concentration in the BAL were determined by a co-worker blinded to the treatment protocol.