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 N-4-quinolinoyl-Gly-(2S)-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 D 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.

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 N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. We have explored the effects of substituting the quinoline ring and varying the position of its sp 2 hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>10 3 ) with respect to both the DPPs and PREP. Preliminary experiments on a representative inhibitor demonstrate that plasma stability, kinetic solubility, and log D of this class of compounds can be expected to be satisfactory.

OBJECTIVES In this randomized split-mouth clinical trial the survival rate and quality of survival of indirect resin composite and ceramic laminate veneers were evaluated. METHODS A total of 48 indirect resin composite (Estenia; n = 24) and ceramic laminate veneers (IPS Empress Esthetic; n = 24) were placed on maxillary anterior teeth. Veneer preparations with incisal overlap were performed using a mock up technique. Survival of the restoration was considered the primary outcome measure and reported using Kaplan-Meier statistics and survival curves compared by means of Log Rank (Mantel-Cox) test. After luting, restorations were evaluated by calibrated operators at baseline and every year thereafter, using modified USPHS criteria and compared by means of Mann-Whitney U test. RESULTS In total, 6 failures were observed, consisting of debonding (n = 3) and fracture (n = 3), all in the group of the indirect resin composite laminate veneers. Cumulative chance on survival after 10 years of the indirect resin composite and ceramic veneers was 75% (se 3,8%) and 100% respectively (p = 0.013). Of the surviving 42 laminate veneers, the variables 'color match' (p = 0.002), 'surface roughness' (p = 0.000), 'fracture of the restoration' (p = 0.028), and 'wear of the restoration' (p = 0.014), were significantly less favourable among the composite laminate veneers as well. CONCLUSIONS The ceramic veneers on maxillary anterior teeth in this study performed significantly better compared to the composite indirect laminate veneers after a decade, both in terms of survival rate and in terms of quality of the surviving restorations. CLINICAL RELEVANCE When indicated, anterior ceramic laminate veneers may be preferred over indirect composite laminate veneers.

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