title: Exploratory Studies With BT-11: A Proposed Orally Active Therapeutic for Crohn's Disease.
abstract: Lanthionine synthetase cyclase-like receptor 2 (LANCL2) is a novel therapeutic target for Crohn's disease (CD). BT-11 is a small molecule that binds LANCL2, is orally active, and has demonstrated therapeutic efficacy in 3 validated mouse models of colitis at doses as low as 8 mg/kg/d. Exploratory experiments evaluated BT-11 in male Harlan Sprague Dawley rats with a single oral dose of 500 mg/kg and 80 mg/kg/d for 14 days (n = 10 rats dosed/group). Treated and control rats were observed for behavioral detriments, and blood and tissues were collected for clinical pathology and histopathological examination. A functional observational battery demonstrated no differences between treated and control groups over multiple times of observation for quantal, categorical, and continuous end points, including posture, in cage activity, approach, response to touch, weight, grip strength, body temperature, and time on a rotarod. Histopathological examination of the brain, kidney, liver, adrenal gland, testes, stomach, small and large intestines, duodenum, pancreas, heart, lungs, spleen, thymus, and rib found no significant differences between the groups. Plasma enzymes associated with liver function were transiently elevated 2 to 4 days after the 500 mg/kg single dose but returned to normal values by 8 days and were not observed at any time in rats given 80 mg/kg/d for 14 days. One hour after oral administration of a single dose of 80 mg/kg, BT-11 had a maximal concentration of 21 ng/mL; the half-life was 3 hours. These experimental results demonstrated that BT-11 is well tolerated in rats, and, with further testing, may hold promise as an orally active therapeutic for CD.
authors.affiliation: Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bissel
authors.affiliation: Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Boes
authors.affiliation: Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hinckley
authors.affiliation: Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA.
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Jortner
authors.affiliation: Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Magnin-Bissel
authors.affiliation: Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Werre
authors.affiliation: Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA marion@vt.edu.
authors.forename: Marion
authors.initials: M
authors.lastname: Ehrich
authors.affiliation: Biotherapeutics Inc, Blacksburg, VA, USA.
authors.forename: Adria
authors.initials: A
authors.lastname: Carbo
authors.affiliation: Biotherapeutics Inc, Blacksburg, VA, USA.
authors.forename: Casandra
authors.initials: C
authors.lastname: Philipson
authors.affiliation: Biotherapeutics Inc, Blacksburg, VA, USA.
authors.forename: Raquel
authors.initials: R
authors.lastname: Hontecillas
authors.affiliation: Biotherapeutics Inc, Blacksburg, VA, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Philipson
authors.affiliation: Biotherapeutics Inc, Blacksburg, VA, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gandour
authors.affiliation: Biotherapeutics Inc, Blacksburg, VA, USA.
authors.forename: Josep
authors.initials: J
authors.lastname: Bassaganya-Riera
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D003424:Crohn Disease / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D023381:Endpoint Determination; D006207:Half-Life; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry; D018675:Toxicity Tests
chemical_list: D001562:Benzimidazoles; C544683:LANCL2 protein, rat; D008565:Membrane Proteins; C000620073:N,N-bis(benzimidazolylpicolinoyl)piperazine; D010879:Piperazines
keywords: BT-11; LANCL2; rats; safety; toxicology