ABSTRACT
INTRODUCTION: Endometrial cancer rates are rising in parallel with the global obesity epidemic. Our aim was to assess the willingness of women at greatest risk of obesity-related endometrial cancer to engage with risk-reducing strategies and establish perceived barriers that may preclude their participation in a randomized controlled trial of primary endometrial cancer prevention. MATERIALS AND METHODS: Women attending gynecology, obesity and sleep apnea clinics in Manchester Academic Health Sciences Centre-affiliated hospitals with obesity classes II (BMI 35-39.9kg/m2) and III (BMI ≥40kg/m2) were invited to participate in a cross-sectional survey. We asked women about their perceived risk, knowledge of risk factors and willingness to engage with endometrial cancer risk-reducing interventions. RESULTS: Seventy-four women with a median age of 51 years (range 22-73) and BMI of 47kg/m2 (range 34-81) took part in the study. Two-thirds (65.6%) knew that obesity was a risk factor for endometrial cancer but few were able to recall other major risk factors. Just over half (53.5%) perceived their risk of developing endometrial cancer to be higher than average. Women were prepared to lose weight (94%), eat healthily (91%), exercise more (87%), take a pill every day (74%) or receive an intra-uterine device (49%) for primary endometrial cancer prevention. Perceived barriers included cost, forgetting, willpower, finding time, physical fitness, social anxiety, possible side effects and previous bad experiences. CONCLUSION: Women at highest risk of obesity-related endometrial cancer may not always appreciate their susceptibility. However, willingness to engage in risk-reducing strategies suggests recruitment to a randomized controlled trial for primary endometrial cancer prevention could be feasible.
ABSTRACT
Lead optimization of piperidine amide HTS hits, based on an anilino-thiazole core, led to the identification of analogs which displayed low nanomolar blocking activity at the canonical transient receptor channels 3 and 6 (TRPC3 & 6) based on FLIPR (carbachol stimulated) and electrophysiology (OAG stimulated) assays. In addition, the anilino-thiazole amides displayed good selectivity over other TRP channels (TRPA1, TRPV1, and TRPV4), as well as against cardiac ion channels (CaV1.2, hERG, and NaV1.5). The high oxidation potential of the aliphatic piperidine and aniline groups, as well as the lability of the thiazole amide group contributed to the high clearance observed for this class of compounds. Conversion of an isoquinoline amide to a naphthyridine amide markedly reduced clearance for the bicyclic piperidines, and improved oral bioavailability for this compound series, however TRPC3 and TRPC6 blocking activity was reduced substantially. Although the most potent anilino-thiazole amides ultimately lacked oral exposure in rodents and were not suitable for chronic dosing, analogs such as 14-19, 22, and 23 are potentially valuable in vitro tool compounds for investigating the role of TRPC3 and TRPC6 in cardiovascular disease.
Subject(s)
Aniline Compounds/chemistry , Aniline Compounds/pharmacology , TRPC Cation Channels/antagonists & inhibitors , Thiazoles/chemistry , Thiazoles/pharmacology , Diglycerides/metabolism , Drug Discovery , HEK293 Cells , Humans , TRPC Cation Channels/metabolism , TRPC6 Cation ChannelABSTRACT
Inhibitors of human methionine aminopeptidase type 2 (hMetAP2) are of interest as potential treatments for cancer. A new class of small molecule reversible inhibitors of hMetAP2 was discovered and optimized, the 4-aryl-1,2,3-triazoles. Compound 24, a potent inhibitor of cobalt-activated hMetAP2, also inhibits human and mouse endothelial cell growth. Using a mouse matrigel model, this reversible hMetAP2 inhibitor was also shown to inhibit angiogenesis in vivo.
