Discovery of Benzo[d]imidazole-6-sulfonamides as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain.

The bromodomain and extra-terminal (BET) family of proteins includes BRD2, BRD3, BRD4, and the testis-specific protein, BRDT, each containing two N-terminal tandem bromodomain (BRD) modules. Potent and selective inhibitors targeting the two bromodomains are required to elucidate their biological role(s), with potential clinical applications. In this study, we designed and synthesized a series of benzimidazole-6-sulfonamides starting from the azobenzene compounds MS436 (7 a) and MS611 (7 b) that exhibited preference for the first (BD1) over the second (BD2) BRD of BET family members.

Discovery and SAR Studies of Orally Active Somatostatin Receptor Subtype-2 (SSTR2) Agonists for the Treatment of Acromegaly.

Acromegaly is a disease caused by the oversecretion of growth hormone. It is currently treated by intravenous injection with cyclic peptide drugs that activate somatostatin receptor subtype 2 (SSTR2). Here, novel nonpeptidic, small-molecule, and orally active SSTR2 agonists were identified from a hit compound ().

Transformation of naltrexone into mesembrane and investigation of the binding properties of its intermediate derivatives to opioid receptors.

We transformed naltrexone (5) with the morphinan skeleton into mesembrane (4) belonging to the Sceletium alkaloids via key intermediate 6, characterized by a cis-fused hydroindole skeleton with a suspended phenyl ring fixed by an epoxy bridge. We then investigated the binding affinities of 4 and the key intermediate 6 derivatives to the opioid receptors. Among the tested compounds, 15', with a cis-fused hydroindole core, bound to the three opioid receptor types with strong to moderate affinities.

Essential structure of opioid κ receptor agonist nalfurafine for binding to the κ receptor 3: synthesis of decahydro(iminoethano)phenanthrene derivatives with an oxygen functionality at the 3-position and their pharmacologies.

To clarify the essential structures of an opioid κ receptor selective agonist, nalfurafine, for binding to the κ receptor, we designed and synthesized the decahydro(iminoethano)phenanthrene derivatives with an oxygen functionality at the 3-position. The introduction of a hydroxy group to the derivatives increased the affinity and selectivity to the κ receptor regardless of the configuration at the 3-position. However, their affinities were lower than those of nalfurafine with the phenolic hydroxy group.

Essential structure of opioid κ receptor agonist nalfurafine for binding to κ receptor 1: synthesis of decahydroisoquinoline derivatives and their pharmacologies.

On the basis of the three-dimensional pharmacophore model of opioid κ agonists, we simplified the structure of nalfurafine (selective κ agonist) to find the essential structural moieties for binding the opioid receptors, especially κ receptor type. As a result, we found that the trans-fused decahydroisoquinoline derivatives without a phenol ring bound the opioid receptor in micromolar order and that both the amide side chain and the nitrogen substituted by the cyclopropylmethyl group were indispensable moieties for eliciting the κ selectivity. The simple decahydroisoquinoline without amide side chain also bound the opioid receptor without receptor type selectivity, suggesting that the message-address concept would be applicable to even these simple derivatives.

Essential structure of opioid κ receptor agonist nalfurafine for binding to the κ receptor 2: synthesis of decahydro(iminoethano)phenanthrene derivatives and their pharmacologies.

To clarify the essential structures of an opioid κ receptor selective agonist, nalfurafine, for binding to the κ receptor, we designed and synthesized some nalfurafine derivatives and the decahydro(iminoethano)phenanthrene derivatives with a cyclohexene moiety as a surrogate for the phenol ring. In addition to the 6-amide side chain and the 17-nitrogen substituted by a cyclopropylmethyl group, the 4,5-epoxy ring, phenolic hydroxy group, and angular hydroxy group played important roles in eliciting the binding properties of nalfurafine but these three moieties were not indispensable for binding to the κ receptor. Moreover, the phenol ring was also not essential for the binding to the κ receptor, and the cyclohexene moiety would play an important role in fixing the conformation of decahydro(iminoethano)phenanthrene derivatives to effectively raise the amide side chain, rendering a conformation that resembled the active one of nalfurafine.

Synthesis of (-)-homogalanthamine from naltrexone.

Acetylcholinesterase inhibitor (-)-homogalanthamine 3 was synthesized from μ opioid antagonist naltrexone (2) in 16% total yield. The synthesis features Grob fragmentation as a key reaction, which was especially accelerated in the presence of 15-crown-5.

Investigation of Beckett-Casy model 2: synthesis of novel 15-16 nornaltrexone derivatives and their pharmacology.

We synthesized novel 15-16 nornaltrexone derivatives 9, 11 and 22 to examine the importance of the cavity in the Beckett-Casy model, which was proposed to interact with the 15-16 ethylene moiety in the morphine structure. All the synthesized compounds showed lower affinities for the opioid receptor than did the naltrexone (10). The binding affinities of 14-OH derivatives 11, in which the rotation of the 9-17 bond would be restricted by an intramolecular hydrogen bond, was improved compared to the corresponding 14-H derivatives 9.

Investigation of Beckett-Casy model 3: synthesis of novel naltrexone derivatives with contracted and expanded D-rings and their pharmacology.

Novel naltrexone derivatives 7 and 8 with contracted and expanded D-rings were synthesized to investigate the importance of orientation of lone electron pair on the nitrogen for binding abilities to the opioid receptor. Compound 7 showed almost no binding affinity, whereas compound 8 was comparable to naltrexone (6) in binding affinity. Conformational analyses and NOE experiments in D(2)O of compounds 6-8 suggested that the lone electron pairs of compounds 6 and 8 with respective six- and seven-membered D-rings would project in the pseudo-axial orientation, whereas compound 7 with five-membered D-ring would have the lone electron pair directing in pseudo-equatorial position.

A double decarboxylation reaction of an oxazolidinone and carboxylic Acid: its application to the synthesis of a new opioid lead compound.

Treatment of oxazolidinone carboxylic acid 6 with potassium carbonate gave olefin 7 by a double decarboxylation reaction. The reaction was proposed to proceed via decarboxylation followed by E1cB-like mechanism. 15,16-Nornaltrexone derivative 17 prepared from double decarboxylation product 7 showed strong affinity for the mu opioid receptor, indicating it to be a new opioid lead compound.

Investigation of Beckett-Casy model 1: synthesis of novel 16,17-seco-naltrexone derivatives and their pharmacology.

Novel 16,17-seco-naltrexone derivatives 3 were synthesized using a 16-17 bond cleavage reaction of naltrexone as the key reaction to examine the Beckett-Casy model. All the prepared 16,17-seco-naltrexone derivatives 3 showed lower affinities for opioid receptors than naltrexone. Although the results of binding assay seem to support the existence of a cavity in the model, further investigation using 15,16-nornaltrexone derivatives 26 will be needed to confirm the model.