Effects of the ACE2 inhibitor GL1001 on acute dextran sodium sulfate-induced colitis in mice.
OBJECTIVE
Angiotensin-converting enzyme 2 (ACE2) is expressed in gastrointestinal tissue. Previous studies of GL1001, a potent and selective ACE2 inhibitor, have revealed anti-inflammatory activity in the mouse digestive tract. We hypothesized that GL1001 might also produce beneficial effects in a mouse DSS model of inflammatory bowel disease.


METHODS
Female mice were used for study.


METHODS
Animals were treated for 5 days with 5% DSS in the drinking water to induce colitis. For the following 9 days, animals were treated twice daily with GL1001 (30, 100, 300 mg/kg, s.c.), sulfasalazine (150 mg/kg, p.o.), or vehicle.


METHODS
Throughout the experiment, body weight, rectal prolapse, stool consistency, and fecal occult blood were monitored. At termination, colon length, histopathology, and myeloperoxidase activity were assessed.


RESULTS
High-dose GL1001 ameliorated DSS-induced disease activity, including rectal prolapse and intestinal bleeding. The most robust effect of GL1001 was observed 48-96 h post DSS treatment and was comparable in magnitude to that of sulfasalazine. Colon pathology and myeloperoxidase activity were also markedly attenuated by high-dose GL1001 treatment, with the most profound effects observed in the distal segment.


CONCLUSIONS
The findings support the previously observed anti-inflammatory effects of ACE2 inhibition in gastrointestinal tissue and suggest that GL1001 may have therapeutic utility for inflammatory bowel disease.
Byrnes
John J
JJ
Drug Repositioning and Selection, Ore Pharmaceuticals, Inc., Cambridge, MA 02139, USA. jbyrnes@orepharma.com
Gross
Stefan
S
Ellard
Courtney
C
Connolly
Kelly
K
Donahue
Stephen
S
Picarella
Dominic
D
D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D003106:Colon / Q000201:enzymology / Q000473:pathology; D016264:Dextran Sulfate / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000473:pathology; D007930:Leucine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011897:Random Allocation
C486469:2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D016264:Dextran Sulfate; D009195:Peroxidase; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D007930:Leucine