UK 370106

IC50: 23 nm (MMP-3)

Stromelysin-1 also known as matrix metalloproteinase-3 (MMP-3) is an enzyme that in humans is encoded by the MMP3 gene. Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix and during tissue remodeling in normal physiological processes, such as embryonic development and reproduction, as well as in disease processes, such as arthritis, and tumour metastasis (http://en.wikipedia.org/wiki/MMP-3).

In vitro: UK-370106, a potent inhibitor of MMP-3 (IC50 ) 23 nM) with >1200-fold weaker potency vs MMP-1, -2, -9, and -14. MMP-13, may contribute to the pathology of chronic wounds. UK-370106 potently inhibited cleavage of [3H]-fibronectin by MMP-3 (IC50 ) 320 nM) but not cleavage of [3H]-gelatin by either MMP-2 or -9 (up to 100 íM). UK-370106 had little effect, at MMP-3 selective concentrations, on keratinocyte migration over a collagen matrix in vitro, which is a model of the re-epithelialization process [1].

In vivo: Following iv (rat) or topical administration to dermal wounds (rabbit), UK-370106 was cleared rapidly (t1/2=23 min) from plasma, but slowly (t1/2 ~ 3 days) from dermal tissue. In a model of chronic dermal ulcers, topical administration of UK-370106 for 6 days substantially inhibited MMP-3 ex vivo. These data suggest UK-370106 is sufficiently potent to inhibit MMP-3-mediated matrix degradation while leaving unaffected cellular migration mediated by MMPs 1, 2, and 9. These properties make UK-370106 a suitable candidate for progression to clinical trials in human chronic dermal wounds, such as venous ulcers [1].

Clinical trial: Pfizer described the discovery of UK-370106, a highly selective peptidicMMP-3 inhibitor, which was identified as a clinical candidate for the topical treatment of chronic dermal ulcers [2], however, it is now still in the preclinical stage and no clinical trial is ongoing.

References:
[1] Fray MJ, Dickinson RP, Huggins JP, Occleston NL.  A potent, selective inhibitor of matrix metalloproteinase-3 for the topical treatment of chronic dermal ulcers. J Med Chem. 2003;46(16):3514-25.
[2] Whitlock GA, Dack KN, Dickinson RP, Lewis ML.  A novel series of highly selective inhibitors of MMP-3. Bioorg Med Chem Lett. 2007;17(24):6750-3.


Conceptualizing the health and well-being impacts of social enterprise: a UK-based study.[Pubmed:28369450]

Health Promot Int. 2018 Oct 1;33(5):748-759.

Social enterprises-businesses that work for social benefit rather than for the maximization of financial returns to shareholders or owners-could potentially prove to be an innovative and sustainable way of tackling 'upstream' social determinants of health. However, empirical work focusing upon how, and to what extent, social enterprise-led activity may impact upon health and well-being is still relatively scarce. This study examines how social enterprises portray their impact, and how such impacts may be considered in health and well-being terms. Through analysing evaluative reports of the work of social enterprises in Scotland (n = 17) utilizing a 'process coding' method, we investigate both the self-reported impacts of the work of social enterprises and the mechanisms by which these are said to be derived. Revisiting previous conceptualizations in the extant literature, this work allows us to present an 'empirically-informed' conceptual model of the health and well-being impacts of social enterprise-led activity, and thus presents a significant advance on previous hypothetical, theoretically-based conceptualizations. It is considered that these findings further improve our overall knowledge of ways in which social enterprise and other parts of the third sector could be considered as potentially valuable 'non-obvious' public health actors.

Cardiovascular causes of maternal sudden death. Sudden arrhythmic death syndrome is leading cause in UK.[Pubmed:28371698]

Eur J Obstet Gynecol Reprod Biol. 2017 May;212:155-159.

OBJECTIVE: This study aims to determine the causes of sudden cardiac death during pregnancy and in the postpartum period and patients' characteristics. There are few studies in the literature. METHODS: Eighty cases of sudden unexpected death due to cardiac causes in relation to pregnancy and postpartum period in a database of 4678 patients were found and examined macroscopically and microscopically. RESULTS: The mean age was 30+/-7 years with a range from 16 to 43 years. About 30% were 35 years old or older; 50% of deaths occurred during pregnancy and 50% during the postpartum period. About 59.18% were obese or overweight where body mass index data were available. The leading causes of death were sudden arrhythmic death syndrome (SADS) (53.75%) and cardiomyopathies (13.80%). Other causes include dissection of aorta or its branches (8.75%), congenital heart disease (2.50%) and valvular disease (3.75%). CONCLUSION: This study highlights sudden cardiac death in pregnancy or in the postpartum period, which is mainly due to SADS with underlying channelopathies and cardiomyopathy. We wish to raise awareness of these frequently under-recognised entities in maternal deaths and the need of cardiological screening of the family as a result of the diagnosis.

Food insecurity and socio-demographic characteristics in two UK ethnic groups: an analysis of women in the Born in Bradford cohort.[Pubmed:28369526]

J Public Health (Oxf). 2018 Mar 1;40(1):32-40.

Background: The use of foodbanks has risen sharply in the UK; however, the epidemiology of UK food insecurity is undeveloped. This study contributes to the field by analysing socio-demographic risk factors for food insecurity in a female, ethnically diverse population. Methods: Data from the Born in Bradford (BiB) cohort were matched with data on food insecurity from the nested BiB1000 study (N = 1280). Logistic regression was used to model food insecurity in relation to ethnicity and socio-demographic factors. Results: Food insecurity, reported by 13.98% of the sample, was more likely among White British than Pakistani women (crude Odds Ratio (OR) 1.94, 95% CI: 1.37; 2.74, adjusted OR 2.37, 95% CI: 1.57; 3.59). In fully adjusted analyses, food insecurity was associated with a range of socio-economic measures, particularly the receipt of mean-tested benefits (adjusted OR 2.11, 95% CI: 1.41; 3.15) and perception of financial insecurity (adjusted OR 8.91, 95% CI: 4.14; 19.16 for finding it difficult/very difficult compared to living comfortably). Conclusions: The finding that food insecurity prevalence may be higher than previously thought and that food insecurity is highly associated with socio-economic status, notably benefit receipt, is a cause for concern necessitating an urgent policy response.

A potent, selective inhibitor of matrix metalloproteinase-3 for the topical treatment of chronic dermal ulcers.[Pubmed:12877590]

J Med Chem. 2003 Jul 31;46(16):3514-25.

The pathology of chronic dermal ulcers is characterized by excessive proteolytic activity which degrades extracellular matrix (required for cell migration) and growth factors and their receptors. The overexpression of MMP-3 (stromelysin-1) and MMP-13 (collagenase-3) is associated with nonhealing wounds, whereas active MMPs-1, -2, -9, and -14 are required for normal wound healing to occur. We describe the synthesis and enzyme inhibition profile of (3R)-3-[([(1S)-2,2-dimethyl-1-(([(1S)-2-methoxy-1-phenylethyl]amino)carbonyl)prop yl]amino)carbonyl]-6-(3-methyl-4-phenylphenyl)hexanoic acid (UK-370,106, 7), which is a potent inhibitor of MMP-3 (IC(50) = 23 nM) with >1200-fold weaker potency vs MMP-1, -2, -9, and -14. MMP-13, which may also contribute to the pathology of chronic wounds, was inhibited about 100-fold less potently by compound 7. Compound 7 potently inhibited cleavage of [(3)H]-fibronectin by MMP-3 (IC(50) = 320 nM) but not cleavage of [(3)H]-gelatin by either MMP-2 or -9 (up to 100 microM). Compound 7 had little effect, at MMP-3 selective concentrations, on keratinocyte migration over a collagen matrix in vitro, which is a model of the re-epithelialization process. Following iv (rat) or topical administration to dermal wounds (rabbit), compound 7 was cleared rapidly (t(1/2) = 23 min) from plasma, but slowly (t(1/2) approximately 3 days) from dermal tissue. In a model of chronic dermal ulcers, topical administration of compound 7 for 6 days substantially inhibited MMP-3 ex vivo. These data suggest compound 7 is sufficiently potent to inhibit MMP-3-mediated matrix degradation while leaving unaffected cellular migration mediated by MMPs 1, 2, and 9. These properties make compound 7 a suitable candidate for progression to clinical trials in human chronic dermal wounds, such as venous ulcers.

UK-370106 is a potent and highly selective MMP-3 (IC50 of 23 nM) and MMP-12 (IC50 of 42 nM) inhibitor with >1200-fold higher potency than MMP-1, MMP-2, MMP-9, and MMP-14, and about 100-fold than MMP-13 and MMP-8. UK-370106 potently inhibits cleavage of [3H]-fibronectin by MMP-3 (IC50 of 320 nM) and has little effect on keratinocyte migration in vitro.

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