Andreas Lerchner

Macrocyclic BACE-1 inhibitors acutely reduce Aβ in brain after po application

A series of macrocyclic peptidic BACE-1 inhibitors was designed. While potency on BACE-1 was rather high, the first set of compounds showed poor brain permeation and high efflux in the MDRI-MDCK assay. The replacement of the secondary benzylamino group with a phenylcyclopropylamino group maintained potency on BACE-1, while P-glycoprotein-mediated efflux was significantly reduced and brain permeation improved. Several compounds from this series demonstrated acute reduction of Abeta in human APP-wildtype transgenic (APP51/16) mice after oral administration.

Ergoline-Derived Inverse Agonists of the Human H3 Receptor for the Treatment of Narcolepsy

Ergoline derivative (6aR,9R)‐4‐(2‐(dimethylamino)ethyl)‐N‐phenyl‐9‐(pyrrolidine‐1‐carbonyl)‐6,6a,8,9‐tetrahydroindolo[4,3‐fg]quinoline‐7(4H)‐carboxamide (1), a CXCR3 antagonist, also inhibits human histamine H3 receptors (H3R) and represents a structurally novel H3R inverse agonist chemotype. It displays favorable pharmacokinetic and in vitro safety profiles, and served as a lead compound in a program to explore ergoline derivatives as potential drug candidates for the treatment of narcolepsy. A key objective of this work was to enhance the safety and efficacy profiles of 1, while minimizing its duration of action to mitigate the episodes of insomnia documented with previously reported clinical candidates during the night following administration. Modifications to the ergoline core at positions 1, 6 and 8 were systematically investigated, and derivative 23 (1‐((4aR,8R,9aR)‐8‐(hydroxymethyl)‐1‐(2‐((R)‐2‐methylpyrrolidin‐1‐yl)ethyl)‐4,4a,7,8,9,9a‐hexahydroindolo[1,14‐fg]quinolin‐6(1H)‐yl)ethanone) was identified as a promising lead compound. Derivative 23 has a desirable pharmacokinetic profile and demonstrated efficacy by enhancing brain concentrations of tele‐methylhistamine, a major histamine metabolite. This validates the potential of the ergoline scaffold to serve as a template for the development of H3R inverse agonists.