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[[File:Contact system.svg|thumb|The two arms of the contact system.]] |
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{{drugbox |
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The two arms of the contact system involve [[factor XII]] (FXII), [[prekallikrein]] (PK) and [[kininogen|high molecular weight kiningogen]] (HK). FXII and PK are [[protease]]s and HK is a non-enzymatic co-factor. In both arms FXII binds to a surface and reciprocal activation of FXII and PK occurs, forming FXIIa and PKa. PK cleaves HK to form cHK, and a peptide is released, known as [[bradykinin]]. BK and its derivatives bind to bradykinin receptors B1 and B2 to mediate [[inflammation]]. Additionally, PK can activate factor XI (FXI), which can initiate the [[coagulation cascade]]. |
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| image = Phortress.png |
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| IUPAC_name = (2S)-2,6-diamino-N-[4-(5-fluoro-1,3-benzothiazol-2-yl)-2-methylphenyl]hexanamide;hydrochloride |
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<!--Clinical data --> |
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| tradename = Phortress |
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<!--Identifiers --> |
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| PubChem = 399464 |
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<!--Chemical data --> |
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| C=20 | H=24| N=4 | O=1 | S=1 | F=1 |Cl=1 |
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| molecular_weight = 422.947 g/mol}} |
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Phortress is a 2-(4-aminophenyl)benzothiazole derivative that is currently in phase-1 [[clinical trial]]s. It was developed from compound CJM 126, which was previously identified in a [[kinase inhibitor]] discovery programme. In order to improve this drug's anti-tumour activity, CJM 126 was derivatised by methylation on its phenolic ring, producing 2-(4-Amino-3-methylphenyl)benzothiazole (DF 203). DF 203 suffered from [[metabolism]] at higher concentrations, so a [[fluorine]] atom was substituted on the [[benzothiazole]] group (producing 5F 203). Finally, to improve its [[solubility]] it was conjugated to [[lysine]], forming the final lysylamide [[prodrug]] for clinical assessment. |
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In cells, the drug is broken down by hydrolysis of the lysylamide group, producing the active drug 5F 203. This binds to the [[aryl hydrocarbon receptor]], activating [[gene transcription|transcription]] of the [[Cytochrome P450, family 1, member A1|''cyp1a1'']] [[gene]]. The enzyme produced from this gene further breaks down 5F 203 into reactive species, which lead to DNA damage and cell death. |
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[[File:CJM126 DF203 5F203.png|thumb|262px|CJM 126, DF 203 and 5F 203]] |
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Revision as of 11:43, 30 July 2018
The two arms of the contact system involve factor XII (FXII), prekallikrein (PK) and high molecular weight kiningogen (HK). FXII and PK are proteases and HK is a non-enzymatic co-factor. In both arms FXII binds to a surface and reciprocal activation of FXII and PK occurs, forming FXIIa and PKa. PK cleaves HK to form cHK, and a peptide is released, known as bradykinin. BK and its derivatives bind to bradykinin receptors B1 and B2 to mediate inflammation. Additionally, PK can activate factor XI (FXI), which can initiate the coagulation cascade.