The applications of fluorine in drug design continue to expand, facilitated by an improved understanding of its effects on physicochemical properties and the development of synthetic methodologies that are providing access to new fluorinated motifs. In turn, studies of fluorinated molecules are providing deeper insights into the effects of fluorine on metabolic pathways, distribution, and disposition. Despite the high strength of the C-F bond, the departure of fluoride from metabolic intermediates can be facile. This reactivity has been leveraged in the design of mechanism-based enzyme inhibitors and has influenced the metabolic fate of fluorinated compounds. In this Perspective, we summarize the literature associated with the metabolism of fluorinated molecules, focusing on examples where the presence of fluorine influences the metabolic profile. These studies have revealed potentially problematic outcomes with some fluorinated motifs and are enhancing our understanding of how fluorine should be deployed.

Metabolic and Pharmaceutical Aspects of Fluorinated Compounds.

γ-Secretase inhibitors and modulators.

An insight on synthetic and medicinal aspects of pyrazolo[1,5-a]pyrimidine scaffold

γ-Secretase modulators as potential disease modifying anti-Alzheimer's drugs.

γ-Secretase is a protease complex responsible for cutting the transmembrane domain of the amyloid β-protein precursor (APP) to form the amyloid β-protein (Aβ), an aggregation-prone product that accumulates in the brain in Alzheimer's disease. As evidence suggests that Aβ is critical to Alzheimer pathogenesis, γ-secretase is considered a key target for the development of disease-modifying therapeutics. The protease complex cuts many other substrates, and some of these proteolytic events are part of signaling pathways or other important cellular functions. Among these, proteolysis of the Notch receptor is essential for signaling that is involved in a number of cell-fate determinations. Many inhibitors of γ-secretase have been identified, but it is clear that drug candidates for Alzheimer's disease should have minimal effects on the Notch signaling pathway, as serious safety issues have arisen with nonselective inhibitors. Two types of promising candidates that target this protease complex have emerged: the so-called "Notch-sparing" γ-secretase inhibitors, which block cleavage of APP selectively over that of Notch, and γ-secretase modulators, which shift the proportion of Aβ peptides produced in favor of shorter, less aggregation-prone species. The current status and prospects for these two general types of candidates will be discussed.

γ-Secretase as a target for Alzheimer's disease.

Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.1S human multiple myeloma xenograft mouse models and has been evaluated as an early development candidate.

Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma.

Fluorinated piperidine acetic acids as γ-secretase modulators

Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design.

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Papers

Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma.

Fluorinated piperidine acetic acids as γ-secretase modulators

Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design.