title: Efficient syntheses of benzothiazepines as antagonists for the mitochondrial sodium-calcium exchanger: potential therapeutics for type II diabetes.
abstract: Type II diabetes mellitus is a chronic metabolic disorder that can lead to serious cardiovascular, renal, neurologic, and retinal complications. While several drugs are currently prescribed to treat type II diabetes, their efficacy is limited by mechanism-related side effects (weight gain, hypoglycemia, gastrointestinal distress), inadequate efficacy for use as monotherapy, and the development of tolerance to the agents. Consequently, combination therapies are frequently employed to effectively regulate blood glucose levels. We have focused on the mitochondrial sodium-calcium exchanger (mNCE) as a novel target for diabetes drug discovery. We have proposed that inhibition of the mNCE can be used to regulate calcium flux across the mitochondrial membrane, thereby enhancing mitochondrial oxidative metabolism, which in turn enhances glucose-stimulated insulin secretion (GSIS) in the pancreatic beta-cell. In this paper, we report the facile synthesis of benzothiazepines and derivatives by S-alkylation using 2-aminobenzhydrols. The syntheses of other bicyclic analogues based on benzothiazepine, benzothiazecine, benzodiazecine, and benzodiazepine templates are also described. These compounds have been evaluated for their inhibition of mNCE activity, and the results from the structure-activity relationship (SAR) studies are discussed.
authors.affiliation: MitoKor, Inc., 11494 Sorrento Valley Road, San Diego, California 92121, USA. peiy@mitokor.com
authors.forename: Yazhong
authors.initials: Y
authors.lastname: Pei
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lilly
authors.forename: David J
authors.initials: DJ
authors.lastname: Owen
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: D'Souza
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Tang
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yu
authors.forename: Ramina
authors.initials: R
authors.lastname: Nazarbaghi
authors.forename: Andrew
authors.initials: A
authors.lastname: Hunter
authors.forename: Christen M
authors.initials: CM
authors.lastname: Anderson
authors.forename: Susan
authors.initials: S
authors.lastname: Glasco
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Ede
authors.forename: Ian W
authors.initials: IW
authors.lastname: James
authors.forename: Uday
authors.initials: U
authors.lastname: Maitra
authors.forename: S
authors.initials: S
authors.lastname: Chandrasekaran
authors.forename: Walter H
authors.initials: WH
authors.lastname: Moos
authors.forename: Soumitra S
authors.initials: SS
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002384:Catalysis; D002478:Cells, Cultured / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D009682:Magnetic Resonance Spectroscopy; D008928:Mitochondria / Q000502:physiology*; D015394:Molecular Structure; D051381:Rats; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D007328:Insulin; D019831:Sodium-Calcium Exchanger; D001569:Benzodiazepines; D002118:Calcium