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Critical Outcome Technologies Inc. Provides Update on Multiple Sclerosis Library 30 March 2007

Critical Outcome Technologies Inc, provided an update to the market today on its Multiple Sclerosis (MS) Library.

Critical Outcome Technologies Inc. (COTI) has been monitoring the synthesis of its first four MS compounds through regular meetings with its synthetic chemistry partner, Dalton Pharma Services (Dalton). "The COTI MS compounds are novel and therefore have not been made before. Each of the first four COTI MS compounds has required the research and development of some entirely new chemistry. As a result, this new chemistry will strengthen our patent position and add to the value realised by future customers" said Dr. Wayne Danter, President and Chief Scientific Officer of COTI.

Dalton has manufactured small amounts of the lead MS compound COT601-M06.1, but has encountered difficulty with scaling up production. Dalton will continue its work synthesising the lead MS compound COT601-M06.1 and is confident that they will be successful in scaling up production.

Since the November 2006 start of the MS molecule synthesis, COTI has broadened its synthetic chemistry resource base in recognition of the complexity and issues surrounding compounds requiring new chemistry. Delmar Chemicals (Delmar)of Montreal has consulted since February 2007 to synthesise the second two MS compounds starting with the lead MS compound COT604-M06.2. Delmaris are also confident that they will be successful in scaling up production.

"COTI together with our synthetic chemistry partners remain confident that these novel compounds will be successfully synthesised in the near future" said Dr. Wayne Danter. "We will continue our pursuit of seeking an effective treatment for acute MS and we will remain focused on engaging prospective partners and customers with this library of novel, optimised lead compounds."

About Critical Outcome Technologies Inc.

COTI is formed around a unique computational platform technology called CHEMSAS®, which allows for the accelerated identification, profiling and optimisation of targeted small molecules potentially effective in the treatment of human diseases for which current therapy is either lacking or ineffective. COTI's business is focused on the discovery and pre-clinical development of libraries of novel, optimised lead molecules for the treatment of specific cancers, HIV and multiple sclerosis. Currently, five targeted libraries of lead compounds (small cell lung cancer, multiple sclerosis, HIV integrase inhibitors, colorectal cancer, and acute myelogenous leukemia in adults) are under active development.

Source: Critical Outcome Technologies Inc.

Critical Outcome Technologies has gone public as of 11/03/08
COTI is working on lead compounds for the oral treatment of acute Multiple Sclerosis.

Their compounds have been engineered to be orally available, have low toxicity, cross the blood brain barrier and selectively inhibit Vascular Endothelial Growth Factor (VEGF-R) and Platelet Derived Growth Factor (PDGF-R) receptor kinases.
They claim their discovery process takes 12-15 months, rather than 5 years, and that they are ready for in vivo testing on their MS drug.
VEGF-R is responsible for endothelial permeability and the breakdown of the BBB.
http://www.criticaloutcome.com/index.htm

AC

so a bit like curcumin

1: Zhonghua Nan Ke Xue. 2008 Feb;14(2):116-21.Links
[Curcumin inhibits the expression of vascular endothelial growth factor and androgen-independent prostate cancer cell line PC-3 in vitro][Article in Chinese]


Deng G, Yu JH, Ye ZQ, Hu ZQ.
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan , Hubei 430030, China. dfg326@sohu.com

OBJECTIVE: To study the effects of curcumin on the expression of the vascular endothelial growth factor (VEGF) and androgen-independent prostate cancer cell line PC-3, and to explore its anticarcinogenic mechanism. METHODS: PC-3 cells were treated with curcumin at the concentration of 0, 6.25, 12.5, 25 and 50 micromol/L respectively. Then the cell activity was assayed by dyed rate of Typan blue and MTT at 12, 24, 36, 48, 72 and 96 hours, the cell cycle and morphological changes observed by flow cytometry (FCM) and electronic microscopy at 24 hours, the VEGF mRNA expression measured by semi-quantitative RT-PCR, and the secreting protein levels of VEGF in the supernatants determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: The growth of PC-3 cells was suppressed obviously by curcumin in a dose- and time-dependent manner in vitro. There were significant differences in inhibition rate among different concentration and time groups (P < 0.01). Furthermore, curcumin arrested the cell cycle of PC-3 cells in the G2/M phase in a dose-dependent manner (P < 0.01). The percentages of apoptotic cells were significantly higher in different concentration groups than in the controls (P < 0.01). Apoptosis-associated morphological changes were observed in PC-3 cells at 24 hours, and a marked decline in the expression of VEGF was noted after the exposure to different concentrations of curcumin within 24 hours. CONCLUSION: Curcumin can suppress the growth of PC-3 cells, promote their apoptosis and arrest their cell cycle in the G2/M phase, and reduce the expression of VEGF mRNA and proteins, which may sever to explain its inhibitory effect on tumor and angiogenesis.

PMID: 18390174 [PubMed - indexed for MEDLINE]

link

1: Curr Neurovasc Res. 2008 Feb;5(1):71-81. Links
Blood brain barrier in hypoxic-ischemic conditions.Kaur C, Ling EA.
Department of Anatomy, Yong Loo Lin School of Medicine, Blk MD10, 4 Medical Drive, National University of Singapore, Singapore 117597. antkaurc@nus.edu.sg.

The blood brain barrier (BBB) plays an important role in the homeostatic regulation of the brain microenvironment and maintains the immune-privileged status of the brain by restricting the entry of T lymphocytes. Structurally, the BBB is formed by tight junctions between the endothelial cells. Astrocytes, pericytes and perivascular microglia surround the endothelial cells contributing to proper functioning of the BBB. Hypoxia, associated with disorders such as stroke, cardiac arrest, respiratory distress, carbon monoxide poisoning among many others, disrupts the BBB. Alterations in the endothelial cells such as increased pinocytotic vesicles and derangement of the tight junction proteins may be responsible for increased permeability at the BBB resulting in swelling of astrocyte end feet. The disruption of BBB in hypoxic conditions is multifactorial and may involve factors such as enhanced production of vascular endothelial growth factor (VEGF), nitric oxide (NO) and inflammatory cytokines. Although future research is needed to look into possible therapeutic strategies to improve the functioning of BBB in hypoxic conditions, experimental studies so far have reported beneficial effect of curcumin, melatonin, simvastatin and minocycline in ameliorating the increased BBB permeability in hypoxic conditions.

PMID: 18289024 [PubMed - in process]

Related ArticlesReviewIn search of the astrocytic factor(s) modulating blood-brain barrier functions in brain capillary endothelial cells in vitro. [Cell Mol Neurobiol. 2005] Blood-retinal barrier in hypoxic ischaemic conditions: Basic concepts, clinical features and management. [Prog Retin Eye Res. 2008] Protein expression of brain endothelial cell E-cadherin after hypoxia/aglycemia: influence of astrocyte contact. [Brain Res. 1999] SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. [Nat Med. 2003] ReviewAstrocyte-endothelial interactions and blood-brain barrier permeability. [J Anat. 2002] » See Reviews... | » See All...

or scutellaria

1: Ai Zheng. 2005 Dec;24(12):1459-63. Links
[Inhibitory effects of Scutellaria barbatae D. Don on tumor angiogenesis and its mechanism][Article in Chinese]


Zhang NN, Bu P, Zhu HH, Shen WG.
Department of Gastroenterology, Subei People's Hospital, Yangzhou, Jiangsu 225001, P. R. China.

BACKGROUND & OBJECTIVE: Various chemically synthetic anti-angiogenesis agents have serious side effects. The traditional Chinese medicine has attracted considerable attention because of its low toxicity. This study was to explore the inhibitory effects of Scutellaria barbatae D. Don, a kind of traditional Chinese medicinal anti-cancer herb, on tumor angiogenesis, and investigate its mechanism. METHODS: Matrigel plug and human umbilical vascular endothelial cells (HUVECs) were used to construct in vivo and in vitro models of angiogenesis to assess the effect of Scutellaria barbatae D. Don on angiogenesis. After cultured with Scutellaria barbatae D. Don, the migration of endothelial cells was examined by Transwell chamber; the expression of vascular endothelial growth factor (VEGF) in HeLa cells was detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Scutellaria barbatae D. Don significantly inhibited angiogenesis in Matrigel; the tube formation number was significantly lower in 20% and 40% medicated serum groups containing Scutellaria barbatae D. Don than in 20% and 40% drug-free serum groups (5.6+/-1.1 vs. 9.8+/-1.3, P=0.001; 1.0+/-0.7 vs. 13.4+/-1.1, P<0.001). Migrated endothelial cells was significantly fewer in 20% and 40% medicated serum groups containing Scutellaria barbatae D. Don than in 20% and 40% drug-free serum groups (19.75+/-2.63 vs. 24.25+/-2.06, P=0.038; 14.00+/-2.58 vs. 26.5+/-4.65, P=0.006). When treated for 24 h and 48 h, the expression of VEGF in HeLa cells was significantly lower in 40% medicated serum group containing Scutellaria barbatae D. Don than in 40% drug-free serum group (138.67+/-9.50 vs. 195.82+/-2.43, P=0.006; 93.84+/-41.11 vs. 193.68+/-18.37, P=0.036). CONCLUSION: Scutellaria barbatae D. Don could efficiently inhibit angiogenesis in tumor tissue which might relate with inhibition of endothelial cell migration and down-regulation of VEGF in tumor cells.

PMID: 16351792 [PubMed - indexed for MEDLINE]