Synthesis, Biological Activity, and SARs of Pyrrolobenzoxazepine Derivatives, a New Class of Specific “Peripheral-Type” Benzodiazepine Receptor Ligands

Abstract

The "peripheral-type" benzodiazepine receptor (PBR) has been reported to play a role in many biological processes. We have synthesized and tested a novel series of PBR ligands based on a pyrrolobenzoxazepine skeleton, in order to provide new receptor ligands. Several of these new compounds proved to be high affinity and selective ligands for PBR, and benzoxazepines 17f and 17j were found to be the most potent ligands for this receptor to have been identified to date. The SAR and the molecular modeling studies detailed herein delineated a number of structural features required for improving affinity. Some of the ligands were employed as "molecular yardsticks" to probe the spatial dimensions of the lipophilic pockets L1 and L3 in the PBR cleft and to determine the effect of occupation of L1 and L3 with respect to affinity, while other C-7 modified analogues provided information specifically on the hydrogen bonding with a putative receptor site H1. The new pyrrolobenzoxazepines were tested in rat cortex, a tissue expressing high density of mitochondrial PBR, and exhibited IC50 and Ki values in the low nanomolar or subnanomolar range, as measured by the displacement of [3H]PK 11195 binding. A subset of the highest affinity ligands was also found to have high affinities for [3H]PK 11195 and [3H]Ro 5-4864 binding in rat adrenal mitochondria. All the ligands in this subset are stimulators of steroidogenesis having similar potency and extent of stimulation as PK 11195 and Ro 5-4864 of steroidogenesis in the mouse Y-1 adrenocortical cell line.

Development of Ligands for the Peripheral Benzodiazepine Receptor

“…OXA-17f and OXA-17j (Fig. 6, Table 3) were reported as the most potent PBR ligands from this series with K i values of 0.26 and 0.36 nM respectively compared to K i value of 0.78 nM for PK 11195 in the same assay [39]. These benzoxazepines were shown to be inactive on GABA A and CBRs and were thus found to be highly selective for the PBR.…”

“…Over the last few decades various PBR pharmacophores have been postulated by different groups [39][40][41] alongside extensive structure activity relationship (SAR) studies. A hydrogenbond donor group (δ1: usually a carbonyl oxygen), two lipophilic regions (PAR and FRA) and another lipophilic region involved in modulating receptor binding (LA) are the general features of the most recently proposed PBR pharmacophore and are said to be necessary for a ligand to interact with the PBR.…”

“…Although these compounds have higher affinity than PK 11195 in both rodent and human cell lines, in vivo pharmacokinetic and pharmacodynamic data is still lacking. PK 11195 --0.78 [39] Almost 15 years ago, when the PBR was referred to as the mitochondrial DBI receptor (MDR), a class of potent (nM) ligands for the PBR were developed by the use of the Fischer indole synthesis and named 2 aryl-3-indoleacetamides (FGIN-1) [50], [61]. These derivatives were found to enhance steroidogenesis and to be highly selective for the PBR as they lacked binding to glycine, glutamate, serotonin and GABA related receptors.…”

Antitumor effect of pyrrolo-1,5-benzoxazepine-15 and its synergistic effect with Oxaliplatin and 5-FU in colorectal cancer cells

“…The 4-acetoxy-5-(1-(naphthyl))naphtho [2,3- ,4] oxazepine (PBOX-15) was synthesized as previously described 16 and dissolved in dimethylsulfoxide (DMSO). The chemotherapeutic agents used were oxaliplatin, kindly provided by Sanofi-Aventis Research, and 5-Fluorouracil (Sigma Aldrich).…”

“…16 In particular, PBOX-15 is a tubulin depolymerizing agent displaying a proapoptotic activity in a variety of human solid and hematological malignancies, [16][17][18][19][20][21] with minimal toxicity toward normal blood and bone marrow cells. 17 In the present study we identified PBOX-15 as a submicromolar selective inhibitor of FAAH enzyme (IC50= 0.843 mM) and we investigated the anti-tumor efficacy and mode of action of this compound on CRC cell lines.…”