ABSTRACT
Quinazolinones 8 and pyrido[3,4-d]pyrimidin-4-ones 9 as orally active and specific matrix metalloproteinase-13 inhibitors were discovered for the treatment of osteoarthritis. Starting from a high-through-put screening (HTS) hit thizolopyrimidin-dione 7, we obtained two chemotypes, 8 and 9, using computer-aided drug design (CADD) and methodical structure-activity relationship (SAR) studies. They occupy the unique S 1'-specificity pocket and do not bind to the Zn(2+) ion. Some pyrido[3,4-d]pyrimidin-4-ones, such as 10a, possess favorable absorption, distribution, metabolism, and elimination (ADME) and safety profiles. 10a effectively prevents cartilage damage in rabbit animal models of osteoarthritis without inducing musculoskeletal side effects when given at extremely high doses to rats.
Subject(s)
Matrix Metalloproteinase Inhibitors , Osteoarthritis/drug therapy , Pyridines/chemical synthesis , Pyrimidines/chemical synthesis , Quinazolinones/chemical synthesis , Administration, Oral , Animals , Biological Availability , Male , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Quinazolinones/pharmacokinetics , Quinazolinones/pharmacology , Rabbits , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The identification of a potent series of IKK-beta selective inhibitors based on an imidazothienopyrazine template and the oral efficacy of one such analog (22j) in the LPS-induced TNF-alpha release mouse model are described.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , I-kappa B Kinase/antagonists & inhibitors , Pyrazines/chemistry , Pyrazines/pharmacology , Animals , Cells, Cultured , Enzyme Inhibitors/chemical synthesis , Humans , Mice , Pyrazines/chemical synthesis , Structure-Activity RelationshipABSTRACT
It has been hypothesized that peripherally restricted NMDA receptor antagonists may be effective analgesics for osteoarthritis pain. A class of novel quinoxalinedione atropisomers, first discovered for an NMDA receptor antagonist program for the treatment of stroke, was evaluated and further optimized with the goal of finding peripherally restricted NMDA receptor antagonists.
Subject(s)
Analgesics/chemistry , Analgesics/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Sulfonamides/chemistry , Sulfonamides/pharmacology , Animals , Area Under Curve , Binding Sites , Models, Molecular , Molecular Structure , Pain/drug therapy , Protein Binding , Rats , Structure-Activity Relationship , Sulfonamides/bloodABSTRACT
Ring-cleaved pleuromutilin derivatives comprised of a [5.3.1] bicyclic core structure have been synthesized and evaluated in vitro as antibacterial agents. Four of the compounds described were found to have MICsSubject(s)
Anti-Bacterial Agents/chemical synthesis
, Anti-Bacterial Agents/chemistry
, Anti-Bacterial Agents/pharmacology
, Diterpenes/chemical synthesis
, Diterpenes/chemistry
, Diterpenes/pharmacology
, Microbial Sensitivity Tests
, Polycyclic Compounds
, Staphylococcus aureus/drug effects
, Streptococcus pneumoniae/drug effects
, Structure-Activity Relationship
, Pleuromutilins
