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Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disease whose pathogenesis cannot be defined by one single element but consists of various factors; thus, there is a call for alternative approaches to tackle the multifaceted aspects of AD. Among the potential alternative targets, we aim to focus on glutaminyl cyclase (QC), which reduces the toxic pyroform of β-amyloid in the brains of AD patients. On the basis of a putative active conformation of the prototype inhibitor 1, a series of N-substituted thiourea, urea, and α-substituted amide derivatives were developed. The structure–activity relationship analyses indicated that conformationally restrained inhibitors demonstrated much improved QC inhibition in vitro compared to nonrestricted analogues, and several selected compounds demonstrated desirable therapeutic activity in an AD mouse model. The conformational analysis of a representative inhibitor indicated that the inhibitor appeared to maintain the Z–E conformation at the active site, as it is critical for its potent activity.

Glutaminyl cyclases (QC, isoQC) convert N-terminal glutamine or glutamate into pyroglutamate (pGlu) on substrates. IsoQC has recently been demonstrated to promote pGlu formation on the N-terminus of CD47, the SIRPα binding site, contributing to the "don't eat me" cancer immune signaling of CD47-SIRPα. We developed new QC inhibitors by applying a structure-based optimization approach starting from fragments identified through library screening. Screening of metal binding fragments identified 5-(1H-benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine ( 9) as a potent fragment, and further modification provided 5-(1-(3-methoxy-4-(3-(piperidin-1-yl)propoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-1,3,4-thiadiazol-2-amine (22b) as a potent QC inhibitor. Treatment with 22b in A549 and H1975 lung cancer cells decreased the CD47/αhCD47-CC2C6 interaction, indicative of the CD47/SIRPα interaction, and enhanced the increased phagocytic activity of both THP-1 and U937 macrophages.

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Patient: Male, 66-year-old Final Diagnosis: Metformin associated lactic acidosis Symptoms: Fatigue • nausea • vomiting • abdominal pain • watery diarrhea Medication: — Clinical Procedure: — Specialty: Critical Care Medicine • Endocrinology and Metabolic • Nephrology Objective: Unusual clinical course Background: Metformin is recommended as the first-line therapy for type 2 diabetes mellitus, according to the American Diabetes Association. It is considered a safe medication with minimal adverse effects, with the most common being gastrointestinal. Metformin-associated lactic acidosis (MALA) is a rare but life-threatening complication. MALA usually occurs in patients with kidney dysfunction. However, it can still occur with preserved kidney function with the ingestion of a large dose of metformin. Case Report: A 66-year-old man with a significant medical history of type 2 diabetes mellitus presented after an intentional ingestion of a high dose of metformin (3000 mg/day). He was admitted to our hospital with symptoms of fatigue, nausea, vomiting, abdominal pain, and watery diarrhea lasting for 3 days. His initial laboratory findings were remarkable, with a serum creatinine level of 819 µmol/L. Arterial blood gas revealed severe lactic acidosis, with a pH of 6.94, HCO 3 – of 3 mEq/L, anion gap of 48 mmol/L, and lactate level of 15 mmol/L. Emergent continuous renal replacement therapy was done. Two days later, his condition improved considerably, and the lactic acidosis was resolved entirely. He was discharged on day 11 of hospitalization. Conclusions: MALA is rare but life-threatening complication of treatment with metformin. MALA should be considered when there is evidence of metformin ingestion and renal insufficiency in patients with lactic acidosis. The curative treatment of MALA is based on hemodialysis, but the main remedy is prevention, which requires patient compliance with taking metformin as prescribed.