Optimization of 1,4-diazepan-2-one containing dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 7, 2007, Pages 1903-1907

  Liang, Gui Bai ^a   Qian, Xiaoxia ^a   Feng, Dennis ^a   Biftu, Tesfaye ^a   Eiermann, George ^a   He, Huaibing ^a   Leiting, Barbara ^a   Lyons, Kathy ^a   Petrov, Aleksandr ^a   Sinha Roy, Ranabir ^a   Zhang, Bei ^a   Wu, Joseph ^a   Zhang, Xiaoping ^a   Thornberry, Nancy A ^a   Weber, Ann E ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

1,4 Diazepan 2 one; DPP IV inhibitors; Type 2 diabetes

Indexed keywords

DIPEPTIDYL PEPTIDASE IV INHIBITOR; KETONE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG EFFICACY; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; IC 50; MALE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; ORAL GLUCOSE TOLERANCE TEST; RAT; SUBSTITUTION REACTION;

ADMINISTRATION, ORAL; ANIMALS; ANTIGENS, CD26; AZEPINES; CHEMISTRY, PHARMACEUTICAL; DIABETES MELLITUS, TYPE 2; DRUG DESIGN; ENZYME INHIBITORS; INHIBITORY CONCENTRATION 50; MALE; MICE; MODELS, CHEMICAL; MOLECULAR CONFORMATION; RATS; RATS, SPRAGUE-DAWLEY;

EID: 33847632984     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.01.039     Document Type: Article

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25. It should be noted that % inhibition as determined using the in vitro assay under estimates the % inhibition achieved in vivo, as compound 14a is a competitive, rapidly reversible inhibitor and assay of plasma DPP-4 activity requires (1) dilution of plasma which results in a dilution of the total inhibitor, and (2) presence of substrate that competes with inhibitor for binding to the enzyme.