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.

Benzothiazepine CGP37157 and Its Isosteric 2′-Methyl Analogue Provide Neuroprotection and Block Cell Calcium Entry

“…The isosteric analogue of CGP37157 where chlorine at position orto of the phenyl ring (C2′) has been replaced by a methyl group (Figure 1), namely, ITH12505, was synthesized according to the experimental procedure described, 36 obtaining ITH12505 with a 58% yield, showing analytical and spectral data according to the literature. 36 Culture of Chromaffin Cells. Adrenal glands were obtained from the city slaughterhouse, under the supervision of the local veterinary service.…”

“…Pei and co-workers have communicated the poor water solubility and short half-life of CGP37157. 36 In that paper, authors describe the efforts to synthesize CGP37157 derivatives, with improved pharmacokinetic profile and mNCX blocking activity, for their use as potential drugs for Type-II diabetes mellitus. Unfortunately, none of the new compounds improved that mNCX blockade elicited by CGP37157, while enhancement of the pharmacokinetic profile was not experimentally demonstrated.…”

“…Focusing on the search of new mNCX ligands for the treatment of AD, we appreciated from the work of Pei and coworkers that the compound numbered as 1c was only 4.5-fold less potent (IC 50 = 6.3 μM) than CGP37157 (IC 50 = 1.4 μM) 36 to block mNCX, and can be considered as the closest isosteric derivative of CGP37157, where the chlorine atom at the pendant phenyl ring has been replaced by a methyl group. Replacement of isosters and bioisosters is a common strategy in medicinal chemistry for the optimization of hit compounds, modulating both pharmacodynamic and pharmacokinetic properties.…”

Benzothiazepine CGP37157 and its 2′-isopropyl analogue modulate Ca2+ entry through CALHM1

“…1), which has been widely used as a mitochondrial Na þ /Ca 2þ exchanger (mNCX) blocker (Chiesi et al, 1988;Pei et al, 2003). This compound and some of its analogues have shown a neuroprotective profile in several in vitro models of AD and stroke (Gonzalez-Lafuente et al, 2012;Nicolau et al, 2009Nicolau et al, , 2010.…”

Friedel-Crafts chemistry. Part 50. Convergent and diversity-oriented constructions of polycyclic quinolines via Friedel-Crafts and Beckmann ring enlargement approaches

“…Another isomerization-RCM strategy was carried out by van Otterlo et al 29 who reported that the synthesis of benzothiazocine dioxide from the corresponding sulfone was carried out in high yield. In an alternative strategy, Lilly et al 30 reported a simple protocol for the synthesis of various benzo-1,4-thiazocines via intramolecular cyclization of acyclic-thioether substrates. Mukherjee et al 31 have applied the same intramolecular cyclization methodology to the synthesis of 2,3,4,5-tetrahydro-2Hbenzo[b] [1,4]thiazocines by treatment of 3-(2-bromophenylthio)propan-1-amines (arenes) with lithium diisopropylamide (LDA).…”