Minghua Sun

The alkaloid conessine and analogues as potent histamine H3 receptor antagonists.

The naturally occurring alkaloid, conessine (6), was discovered to bind to histamine H3 receptors in a radioligand-based high-throughput screen. Conessine displayed high affinity at both rat and human H3 receptors (pKi = 7.61 and 8.27) and generally high selectivity against other sites, including histamine receptors H1, H2, and H4. Conessine was found to efficiently penetrate the CNS and reach very high brain concentrations. Although the very slow CNS clearance and strong binding to adrenergic receptors discouraged focus on conessine itself for further development, its potency and novel steroid-based skeleton motivated further chemical investigation. Modification based on introducing diversity at the 3-nitrogen position generated a new series of H3 antagonists with higher in vitro potency, improved target selectivity, and more favorable drug-like properties. One optimized analogue (13c) was examined in detail and was found to be efficacious in animal behavioral model of cognition.

Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious γ-secretase inhibitors (Part II)

Significant improvement in metabolic stability on the pyrazolopiperidine scaffold over the original series were achieved and this stability improvement translated in an improved in vivo efficacy.

Design, synthesis and structure-activity relationship of novel [3.3.1] bicyclic sulfonamide-pyrazoles as potent γ-secretase inhibitors.

The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate β-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by γ-secretase, are highlighted.

Design of a new histamine H3 receptor antagonist chemotype: (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrroles, synthesis, and structure-activity relationships.

A new histamine H3 receptor (H3R) antagonist chemotype 1 was designed by combining key pharmacophoric elements from two different precursor structural series and then simplifying and optimizing the resulting combined structural features. First, analogues were made based on a previously identified conessine-based H3R antagonist series. While the first analogues 11 and 15 showed no antagonistic activity to H3R, the mere addition of a key moiety found in the reference compound 7 (ABT-239) elevated the series to high potency at H3R. The hybrid structure (16b) was judged too synthetically demanding to enable an extensive SAR study, thus forcing a strategy to simplify the chemical structure. The resulting (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrrole series proved to be highly potent, as exemplified by 17a having a human H3 K(i) of 0.54 nM, rat H3 K(i) of 4.57 nM, and excellent pharmacokinetics (PK) profile in rats (oral bioavailability of 39% and t(1/2) of 2.4 h).

Discovery of a novel [3.2.1] benzo fused bicyclic sulfonamide-pyrazoles as potent, selective and efficacious γ-secretase inhibitors

Structure-activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted.