Efficient syntheses of benzothiazepines as antagonists for the mitochondrial sodium-calcium exchanger: potential therapeutics for type II diabetes.
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.
Pei
Yazhong
Y
MitoKor, Inc., 11494 Sorrento Valley Road, San Diego, California 92121, USA. peiy@mitokor.com
Lilly
Michael J
MJ
Owen
David J
DJ
D'Souza
Lawrence J
LJ
Tang
Xiao-Qing
XQ
Yu
Jinghua
J
Nazarbaghi
Ramina
R
Hunter
Andrew
A
Anderson
Christen M
CM
Glasco
Susan
S
Ede
Nicholas J
NJ
James
Ian W
IW
Maitra
Uday
U
Chandrasekaran
S
S
Moos
Walter H
WH
Ghosh
Soumitra S
SS
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
D007328:Insulin; D019831:Sodium-Calcium Exchanger; D001569:Benzodiazepines; D002118:Calcium