Quinazolinones and Pyrido[3,4-d]pyrimidin-4-ones as Orally Active and Specific Matrix Metalloproteinase-13 Inhibitors for the Treatment of Osteoarthritis

• Published in: Journal of medicinal chemistry Vol. 51; no. 4; pp. 835 - 841
• Main Authors: Li, Jie Jack, Nahra, Joe, Johnson, Adam R, Bunker, Amy, O’Brien, Patrick, Yue, Wen-Song, Ortwine, Daniel F, Man, Chiu-Fai, Baragi, Vijay, Kilgore, Kenneth, Dyer, Richard D, Han, Hyo-Kyung
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.02.2008; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Biological Availability; Bones, joints and connective tissue. Antiinflammatory agents; Chemistry, Medicinal; Life Sciences & Biomedicine; Male; Matrix Metalloproteinase Inhibitors; Medical sciences; Osteoarthritis - drug therapy; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyridines - chemical synthesis; Pyridines - pharmacokinetics; Pyridines - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Quinazolinones - chemical synthesis; Quinazolinones - pharmacokinetics; Quinazolinones - pharmacology; Rabbits; Rats; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; CELL LUNG-CANCER; RHEUMATOID-ARTHRITIS; CARBOPLATIN; COLLAGENASE-3 MMP-13; II COLLAGEN; ARTICULAR-CARTILAGE; CLONING; COLLAGENOLYTIC ACTIVITY; EXPRESSION; MARIMASTAT; Rat; Quinazoline derivatives; Diseases of the osteoarticular system; Rabbit; Metalloendopeptidases; Benzoic acid derivatives; Structure activity relation; Degenerative disease; Absorption Distribution Metabolisme Excretion; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; Lagomorpha; In vitro; Peptidases; In vivo; Vertebrata; Mammalia; Treatment; Animal; Arthropathy; Hydrolases; Pharmacokinetics; Osteoarthritis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm701274v

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 S1′-specificity pocket and do not bind to the Zn2+ 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.