Jonathan Bowyer

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OBJECTIVE To characterise longitudinal changes in joint integrity and cartilage volume in vivo in the guinea pig spontaneous osteoarthritis (OA) model by magnetic resonance imaging (MRI). METHODS Guinea pigs knee were imaged in vivo by high-resolution three-dimensional (3D) MRI between the ages of 3 and 12 months. Image analysis was performed to assess(More)
The role of cathepsin L in normal physiological processes was assessed using cathepsin L homozygous knockout mice (B6;129-Ctsl(tm1Alpk)). These mice were generated using gene targeting in embryonic stem cells. Null mice fail to express mRNA and protein to cathepsin L. They developed normally and were fertile. The distinct phenotypic change exhibited was a(More)
Potent inhibition of Janus kinase 3 was found for a series of naphthyl(beta-aminoethyl)ketones (e.g. 7, pIC50 = 7.1+/-0.3). Further studies indicated that these compounds fragment in less than 1 h by retro-Michael reaction in the Jak3 in vitro ELISA assay procedure. The breakdown product of 7, 2-naphthylvinyl ketone (22, pIC50 = 6.8+/-0.3) showed very(More)
Cathepsin K is a cysteine proteinase which is believed to contribute to osteoarthritis (OA) pathogenesis. This brief report evaluates the effect of the novel selective cathepsin K inhibitor AZ12606133 on cartilage metabolism in the Dunkin-Hartley guinea pig model of spontaneous OA. In parallel, electrophysiological studies were performed to determine(More)
The objective was to assess the effect of doxycycline treatment on a magnetic resonance imaging (MRI) biomarker of cartilage volume loss, and on matrix metalloproteinase (MMP) activity in a guinea pig osteoarthritis model. Guinea pigs (9 months old) were dosed with vehicle or doxycycline, 0.6, 3.0 mg/kg/day for 66 days. Fat-suppressed 3D gradient-echo MRI(More)
A 42-year-old white female, who had an acute myocardial infarction, developed postinfarction angina and underwent coronary angiography seven weeks after the event. Coronary angiogram demonstrated a primary dissection of the left anterior descending artery. To our knowledge this is the sixth such report of a patient with primary dissection of a coronary(More)
OBJECTIVE We have previously described angiogenesis at the osteochondral junction and in synovium of knees from patients with osteoarthritis (OA), but little is known about how closely animal models of OA resemble human disease with respect to vascular growth. This study aimed to characterise two animal models of knee OA with particular respect to(More)
OBJECTIVE To investigate the effects of a matrix metalloproteinase (MMP) inhibitor on joint pathology and pain behavior in the rat meniscal transection (MNX) model of osteoarthritis (OA) and evaluate which aspects of structural disease modification contribute to symptom improvement. METHODS OA pathology was induced in male Lewis rats, by transecting the(More)
Rational structure-based design has yielded highly potent inhibitors of cathepsin K (Cat K) with excellent physical properties, selectivity profiles, and pharmacokinetics. Compounds with a 3,4-(CH₃O)₂Ph motif, such as 31, were found to have excellent metabolic stability and absorption profiles. Through metabolite identification studies, a reactive(More)
Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this(More)