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Synthesis and structure-activity studies on inhibitors of Tripeptidyl peptidase II

Samad, Sanjeeda; (2000) Synthesis and structure-activity studies on inhibitors of Tripeptidyl peptidase II. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Sulphated cholecystokinin-8 (CCK-8) is an octapeptide neurotransmitter responsible for a variety of biological effects including the induction of satiety (loss of appetite). The control of food intake is mediated by the CCKA receptor subtype. Despite the interest for a CCKA agonist as a potential pro-satiating drug in the treatment of obesity, no such agent to date with acceptable bioavailability has been developed. Levels of CCK-8 are regulated by an enzyme which has only recently been identified as Tripeptidyl peptidase II (TPP II). A selective peptidase inhibitor has been designed that protects CCK-8 against inactivation such that CCK-8 levels are amplified enough to suppress appetite. Butabindide was reported in 1996 as a potent and specific inhibitor of TPP II. Active in vivo, reducing food intake in starved mice, butabindide is an important pharmacological tool as an anti-obesity agent. This thesis provides a complete account of the design, synthesis, and pharmacological activity of butabindide and additional analogues. This work focuses on modifying the structure of butabindide with the aim of improving its oral activity and to further increase inhibitor potency. As well as gaining a better insight into the nature of the TPP II binding subsites. Subsequent structure-activity studies showed the importance of the aminobutyryl residue. When replaced with other aminoacids activity was reduced. More potent inhibitors were achieved by introduction of a trifluoroethyl group at the indoline amide side chain together with substitution at positions 4 or 5 of the indoline ring. The best compound so far, UCL 2000 is 18 times as potent in vitro and 50 times as active in vivo than butabindide.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Synthesis and structure-activity studies on inhibitors of Tripeptidyl peptidase II
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Pure sciences; Health and environmental sciences; Butabindide
URI: https://discovery.ucl.ac.uk/id/eprint/10105668
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