Early Development Scale-Up of a Structurally-Challenging 5‑Lipoxygenase Activating Protein (FLAP) Inhibitor

A practical and efficient synthesis of the FLAP inhibitor <b>1</b> was developed addressing multiple scale-up and safety concerns posed by the established synthesis and utilized a resolution strategy (replacing supercritical fluid chromatography (SFC) separation) for expedient access to the key structural component of <b>1</b>: the challenging chiral quaternary center. Also highlighted are in situ IR monitoring, condensation to form the 1,2,4-oxadiazole ring, and an efficient Suzuki-Miyaura coupling

Discovery of PiragliatinFirst Glucokinase Activator Studied in Type 2 Diabetic Patients

Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound <b>1</b>, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, <b>2</b>. Subsequent SAR studies of <b>1</b> led to the identification of a pyrazine-based lead analogue <b>3</b>, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of <b>3</b>, led to the selection of piragliatin, <b>4</b>, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase β-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D

Discovery of PiragliatinFirst Glucokinase Activator Studied in Type 2 Diabetic Patients

Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound <b>1</b>, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, <b>2</b>. Subsequent SAR studies of <b>1</b> led to the identification of a pyrazine-based lead analogue <b>3</b>, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of <b>3</b>, led to the selection of piragliatin, <b>4</b>, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase β-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D

Development of an Asymmetric Synthesis of a Chiral Quaternary FLAP Inhibitor

A practical sequence involving a noncryogenic stereospecific boronate rearrangement followed by a robust formylation with an in situ generated DCM anion has been developed for the asymmetric construction of an all-carbon quaternary stereogenic center of a FLAP inhibitor. The key boronate rearrangement was rendered noncryogenic and robust by using LDA as the base and instituting an in situ trapping of the unstable lithiated benzylic carbamate with the boronic ester. A similar strategy was implemented for the DCM formylation reaction. It was found that the 1,2-boronate rearrangement for the formylation reaction could be temperature-controlled, thus preventing overaddition of the DCM anion and rendering the process reproducible. The robust stereospecific boronate rearrangement and formylation were utilized for the practical asymmetric synthesis of a chiral quaternary FLAP inhibitor

Synthesis, SAR, and Series Evolution of Novel Oxadiazole-Containing 5‑Lipoxygenase Activating Protein Inhibitors: Discovery of 2‑[4-(3-{(<i>R</i>)‑1-[4-(2-Amino-pyrimidin-5-yl)-phenyl]-1-cyclopropyl-ethyl}-[1,2,4]oxadiazol-5-yl)-pyrazol-1-yl]‑<i>N</i>,<i>N</i>‑dimethyl-acetamide (BI 665915)

The synthesis, structure–activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC₅₀ < 10 nM) and potent inhibition of LTB₄ synthesis in human whole blood (IC₅₀ < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound <b>69</b> (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, <b>69</b> was predicted to have a low risk for potential drug–drug interactions due to its cytochrome P450 3A4 profile. In a murine <i>ex vivo</i> whole blood study, <b>69</b> demonstrated a linear dose–exposure relationship and a dose-dependent inhibition of LTB₄ production