ABSTRACT
IMPORTANCE OF THE FIELD: Aggrecanases are members of a disintegrin and metalloprotease with thrombospondin motif family of zinc metalloproteases involved in the cleavage of aggrecan fragments in cartilage. Inhibition of aggrecanase activity in osteoarthritis (OA) patients should both provide symptomatic relief of OA pain as well as OA disease modification. AREAS COVERED IN THIS REVIEW: This article reviews patent applications containing compounds claimed to have aggrecanase inhibitory activity which were published from 2005 through August 2010. WHAT THE READER WILL GAIN: Readers will be informed of the different classes of disclosed aggrecanase inhibitors and gain an understanding of how these series interact with the various components of the catalytic sites of these enzymes. TAKE HOME MESSAGE: Patenting in the area of aggrecanase inhibitors has been modest. Most of the patented chemical matter are lipophilic, acidic compounds with molecular mass (MM) > 400: properties that usually do not imbue good systemic compound exposure. Possibly due to these properties and poor exposure, there are no late state aggrecanase compounds in the clinic to our knowledge. The future development of lower MM, less acidic aggrecanase inhibitors with good pharmacokinetic profiles could increase activity in this field as aggrecanases are well-validated targets for diseases such as OA.
Subject(s)
Endopeptidases/drug effects , Osteoarthritis/drug therapy , Protease Inhibitors/pharmacology , Animals , Drug Delivery Systems , Drug Design , Endopeptidases/metabolism , Humans , Hydrogen-Ion Concentration , Osteoarthritis/physiopathology , Patents as Topic , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokineticsSubject(s)
Drug Design , Mutation , Neoplasms/enzymology , Phosphotransferases/genetics , Amino Acid Sequence , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Humans , Molecular Sequence Data , Neoplasms/drug therapy , Phosphotransferases/antagonists & inhibitors , Phosphotransferases/chemistry , Protein ConformationABSTRACT
Aminopyrimidine 2 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-cyclopropylpyrimidin-2-amine) emerged from a high throughput screen as a novel 5-HT(1A) agonist. This compound showed moderate potency for 5-HT(1A) in binding and functional assays, as well as moderate metabolic stability. Implementation of a strategy for improving metabolic stability by lowering the lipophilicity (cLogD) led to identification of methyl ether 31 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-(2-methoxyethyl)pyrimidin-2-amine) as a substantially improved compound within the series.
