Introduction:The search for drugs to treat Alzheimer's disease (AD) has failed to yield effective therapies. Here we report the first genome-wide search for biomarkers associated with therapeutic response in AD. Blarcamesine (ANAVEX2-73), a selective sigma-1 receptor (SIGMAR1) agonist, was studied in a 57-week Phase 2a trial (NCT02244541).The study was extended for a further 208 weeks (NCT02756858) after meeting its primary safety endpoint. Methods: Safety, clinical features, pharmacokinetic, and efficacy, measured by changes in the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL), were recorded. Whole exome and transcriptome sequences were obtained for 21 patients. The relationship between all available patient data and efficacy outcome measures was analyzed with unsupervised formal concept analysis (FCA), integrated in the Knowledge Extraction and Management (KEM) environment.Results: Biomarkers with a significant impact on clinical outcomes were identified at week 57: mean plasma concentration of blarcamesine (slope MMSE:P < .041), genomic variants SIGMAR1 p.Gln2Pro (ΔMMSE:P < .039; ΔADCS-ADL:P < .063) and COMT p.Leu146fs (ΔMMSE:P < .039; ΔADCS-ADL:P < .063), and baseline MMSE score (slope MMSE:P < .015). Their combined impact on drug response was confirmed at week 148 with linear mixed effect models.

No abstract

Fragile X syndrome (FXS), a disorder of synaptic development and function, is the most prevalent genetic form of intellectual disability and autism spectrum disorder. FXS mouse models display clinically-relevant phenotypes, such as increased anxiety and hyperactivity. Despite their availability, so far advances in drug development have not yielded new treatments. Therefore, testing novel drugs that can ameliorate FXS’ cognitive and behavioral impairments is imperative. ANAVEX2-73 (blarcamesine) is a sigma-1 receptor (S1R) agonist with a strong safety record and preliminary efficacy evidence in patients with Alzheimer’s disease and Rett syndrome, other synaptic neurodegenerative and neurodevelopmental disorders. S1R’s role in calcium homeostasis and mitochondrial function, cellular functions related to synaptic function, makes blarcamesine a potential drug candidate for FXS. Administration of blarcamesine in 2-month-old FXS and wild type mice for 2 weeks led to normalization in two key neurobehavioral phenotypes: open field test (hyperactivity) and contextual fear conditioning (associative learning). Furthermore, there was improvement in marble-burying (anxiety, perseverative behavior). It also restored levels of BDNF, a converging point of many synaptic regulators, in the hippocampus. Positron emission tomography (PET) and ex vivo autoradiographic studies, using the highly selective S1R PET ligand [18F]FTC-146, demonstrated the drug’s dose-dependent receptor occupancy. Subsequent analyses also showed a wide but variable brain regional distribution of S1Rs, which was preserved in FXS mice. Altogether, these neurobehavioral, biochemical, and imaging data demonstrates doses that yield measurable receptor occupancy are effective for improving the synaptic and behavioral phenotype in FXS mice. The present findings support the viability of S1R as a therapeutic target in FXS, and the clinical potential of blarcamesine in FXS and other neurodevelopmental disorders.

The following chiral organometallic complexes of the cinchona alkaloids quinine (L1), cinchonidine (L2), quinidine (L3), cinchonine (L4) were prepared: [(η5‐C5H5)(Ph3P)(OC)‐Ru(L)]BF4 (1: L=L1; 2: L=L2; 3: L=L3), ClAuL1 (4), [(η5‐C5Me5)(Cl2)Ir(L)] (5: L=L1; 6: L=L2; 7: L=L4), [(η5‐C5Me5)(Cl2)Rh(L2)] (8), [(η6‐p‐cymene)(Cl2)Ru(L)] (9: L=L1; 10: L=L2; 11: L=L4). In all complexes the tertiary nitrogen atom of the cinchona alkaloids is bound to the metal. Complexes 5 – 11 are formed as mixtures of isomers. Elimination of HCl from 10 and 11 gives the neutral N,O‐chelate complexes (η6‐p‐cymene)(Cl)Ru(L2 – H+) (13) and (η6‐p‐cymene)‐(Cl)Ru(L4 – H+) (14) which were structurally characterized by X‐ray diffraction.

The organometallic Lewis acids (OC)sRe+ and Cp(OCXPhsP)Ru+ form adducts with the 0-and N-donors H,O, EtOH, THF, acetone, CHsCN, carboxylic esters, NCCHzCOzMe, BrCH,CO,Me, y-valerolactone, &valerolactam, r-caprolactam, benzophenone imine. The chiral ethanol complex [CpfOCXPh,P)Ru(HOEt)]+BF,t-crystallizes as pairs of enantiomers S,S, and R,,R, and the single crystal X-ray determination shows a hydrogen bridge between the oxygen atom of coordinated ethanol and the tetrafluoroborate anion. ZusammenfassungDie metallorganischen Lewisssluren (OC)sRe+ und Cp(OCXPhsP)Ru+ bilden Addukte mit den 0-bzw.