2 research outputs found
Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold
Fibroblast
activation protein (FAP) is a serine protease that is generally accepted
to play an important role in tumor growth and other diseases involving
tissue remodeling. Currently there are no FAP inhibitors with reported
selectivity toward both the closely related dipeptidyl peptidases
(DPPs) and prolyl oligopeptidase (PREP). We present the discovery
of a new class of FAP inhibitors with a <i>N</i>-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine)
scaffold. We have explored the effects of substituting the quinoline
ring and varying the position of its sp<sup>2</sup> hybridized nitrogen
atom. The most promising inhibitors combined low nanomolar FAP inhibition
and high selectivity indices (>10<sup>3</sup>) with respect to
both the DPPs and PREP. Preliminary experiments on a representative
inhibitor demonstrate that plasma stability, kinetic solubility, and log <i>D</i> of this class of compounds can be expected to be satisfactory
Extended Structure–Activity Relationship and Pharmacokinetic Investigation of (4-Quinolinoyl)glycyl-2-cyanopyrrolidine Inhibitors of Fibroblast Activation Protein (FAP)
Fibroblast activation protein (FAP)
is a serine protease related to dipeptidyl peptidase IV (DPPIV). It
has been convincingly linked to multiple disease states involving
remodeling of the extracellular matrix. FAP inhibition is investigated
as a therapeutic option for several of these diseases, with most attention
so far devoted to oncology applications. We previously discovered
the <i>N</i>-4-quinolinoyl-Gly-(2<i>S</i>)-cyanoPro
scaffold as a possible entry to highly potent and selective FAP inhibitors.
In the present study, we explore in detail the structure–activity
relationship around this core scaffold. We report extensively optimized
compounds that display low nanomolar inhibitory potency and high selectivity
against the related dipeptidyl peptidases (DPPs) DPPIV, DPP9, DPPII,
and prolyl oligopeptidase (PREP). The log <i>D</i> values,
plasma stabilities, and microsomal stabilities of selected compounds
were found to be highly satisfactory. Pharmacokinetic evaluation in
mice of selected inhibitors demonstrated high oral bioavailability,
plasma half-life, and the potential to selectively and completely
inhibit FAP in vivo