Inhibitors of tripeptidyl peptidase II. 3. Derivation of butabindide by successive structure optimizations leading to a potential general approach to designing exopeptidase inhibitors.
The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase that has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO3H)-Met-OH + Gly-Trp-Met-Asp-Phe-NH2. Starting from Val-Pro-NHBu, a dipeptide of submicromolar affinity that had previously been generated to serve as a lead, successive optimization at P3, P1, and then P2 gave Abu-Pro-NHBu (18, Ki = 80 nM). Further transformation (by making a benzologue) gave the indoline analogue, butabindide (33) as a reversible inhibitor having nanomolar affinity (Ki = 7 nM). Retrospective analysis suggested the possibility of a general approach to designing exopeptidase inhibitors starting from the structure of the first hydrolysis product. Application of this approach to CCK-8 led to Abu-Phe-NHBu (37), but this only had Ki = 9.4 microM. Molecular modeling, to determine the minimum energy conformations and explain the 1000-fold better affinity of butabindide, indicated that 37 cannot access the likely active conformation of butabindide.
Ganellin
C Robin
CR
Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, England. c.r.ganellin@ucl.ac.uk
Bishop
Paul B
PB
Bambal
Ramesh B
RB
Chan
Suzanne M T
SM
Leblond
Bertrand
B
Moore
Andrew N J
AN
Zhao
Lihua
L
Bourgeat
Pierre
P
Rose
Christiane
C
Vargas
Froylan
F
Schwartz
Jean-Charles
JC
D000626:Aminopeptidases; D000818:Animals; D002540:Cerebral Cortex / Q000201:enzymology; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012844:Sincalide / Q000378:metabolism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D007211:Indoles; D007527:Isoenzymes; D015842:Serine Proteinase Inhibitors; C098807:butabindide; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases; D012844:Sincalide