4-Acyl-1-(4-aminoalkoxyphenyl)-2-ketopiperazines as a Novel Class of Non-Brain-Penetrant Histamine H₃ Receptor Antagonists

Abstract

A series of ketopiperazines were prepared and evaluated for their activity as histamine H 3 antagonists. From investigation of the tertiary basic center in the aminopropyloxyphenyl template, the 2( R)-methylpyrrolidine was identified as the most potent amine. In the more rigid piperidineoxyphenyl template the N-cyclobutyl group was the most potent amine. The 4-fluorobenzyol, 4-cyanobenzoyl, and 2,4-difluorobenzoyl groups provided good pharmacokinetic profiles for the various amides. The PSA and log D values of these compounds suggested low brain penetration. The compounds had very high selectivity over other receptors and did not inhibit hepatic cytochrome P450, indicating low drug-drug interaction potential. Compound 22i was identified as the best compound of this series based on its overall profile of high potency, selectivity, low brain penetration, lack of CYP450 inhibition, high oral bioavailability, and pharmacokinetic properties.

Diamine ligands in copper-catalyzed reactions

“…At GlaxoSmithKline researchers investigated the amidation of an aryl iodide in the synthesis of non-brain-penetrant histamine H 3 receptor antagonists for the treatment of allergy conditions (Scheme 42). 177 The Cu-catalyzed vinylation of amides is also apposite in medicinal chemistry. Scientists at Bristols-Myers Squibb exploited diamine ligands in the Cu-catalyzed synthesis of enamides with aminopeptidase activity from a-amino amides (Scheme 43).…”

Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and Dihydropyrazinones from Polymer‐Supported Acyclic Intermediates via N‐Alkyl‐ and N‐Acyl­iminiums

“…Iminium chemistry has been reviewed in several excellent papers 6–9. Alternative routes from the analogous acyclic precursors by C–N bond formation include cyclization of mesylates 5 with the amide nitrogen10 and Mitsunobu alkylation between the amide and alcohol functions of precursor 6 11. Amine – alcohol cyclization has also been reported 2…”

Using Graph Databases to Investigate Trends in Structure–Activity Relationship Networks

“…In a second example, a quartet of ketopiperazine analogs as histamine H3 receptor antagonists is shown in Figure (upper right) . Replacing the homopiperidine ring in CHEMBL400612 (A, pIC 50 4.900) by a methylpyrrolidine ring (MMP1) results in CHEMBL239080 (A1, pIC 50 4.200).…”