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Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a very potent 5-HT7 receptor antagonist (Ki = 153 pM), with slightly lesser potency toward 5-HT6, 5-HT2A, and 5HT-2C receptors (Ki = 1.2-2.0 nM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Ki = 0.58 nM) and adrenergic α2A, α2B, and α2C (Ki = 0.41-3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer's disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis.

2014-08-01·CNS Spectrums3区 · 医学

Add-on clinical effects of selective antagonist of 5HT6 receptors AVN-211 (CD-008-0173) in patients with schizophrenia stabilized on antipsychotic treatment: pilot study

3区 · 医学

Article

作者: Beniashvily, Allan G ; Kazey, Vasily I ; Lepilkina, Taisiya A ; Bondarenko, Evgeny V ; Morozova, Margarita A ; Ivachtchenko, Alexandre V ; Rupchev, Georgy E ; Burminskiy, Denis S ; Lavrovsky, Yan ; Potanin, Sergey S

The serotoninergic system as a target for add-on treatment seems to be a promising approach in patients with schizophrenia.ObjectiveTo clarify if selective 5HT-6 antagonist AVN-211 (CD-008-0173) adds clinical and cognitive effects to stable antipsychotic treatment.MethodsA randomized, double-blind, placebo-controlled, add-on, 4r-week trial in 47 schizophrenia patients (21 patients receiving study drug and 26 receiving placebo) who were stabilized on antipsychotic medication was performed. Seventeen patients from the study drug group and 25 patients from the placebo group completed the trial. Treatment effects were measured using clinical rating scales and attention tests.ResultsWith no differences at baseline, there was a significant difference between the groups in Positive and Negative Syndrome Scale (PANSS) positive subscale score (p = 0.058) in favor of patients in the treatment group at the endpoint. The PANSS positive subscore (p = 0.0068) and Clinical Global Impression–Severity (CGI-S) (p = 0.048) score significantly changed only in the treatment group. Only in the placebo group were significant changes in Calgary Depression Rating Scale (CDRS) total score registered. The indices of attention tests at endpoint did not show differences between the groups, with the exception of the scope of change in the results of the subtest VIII of the Wechsler Adult Intelligence Scale (WAIS), which showed difference between the groups (p = 0.02) and was significantly larger in the treatment group. Only inside the study drug group, significant changes in selectivity and continuous attention were observed regarding total correct responses (p = 0.0038) and reaction time (p = 0.058) in the Continuous Attention Task (CAT) test.ConclusionSelective 5HT6 antagonist AVN-211 (CD-008-0173) added antipsychotic and some procognitive (attention) effects to antipsychotic medication.

2010-07-01·Alzheimer's & Dementia

P3‐442: Preclinical and early clinical studies of AVN‐101, a novel balanced molecule for the treatment of Alzheimer's disease

作者: Morozova, M. ; Kasey, V. ; Salimov, R.M. ; Ivachtchenko, Alexander V. ; Lavrovsky, Yan

to reduce the potential toxicity of an immune response to a normal self protein. Methods: We used active immunization with aggregated British amyloid (ABri) related peptides in a predominantly b-sheet conformation alone or in combination with related immunogens. ABri is a rare form of familial human amyloidosis associated with a mis-sense mutation in a stop codon resulting in the production of a highly amyloidogenic protein with no sequence homology to other native human proteins. This immunization was done in APP/PS1 Tg mice, vascular amyloid model Tg SwDI mice and in 3x Tg mice with both tau and amyloid pathology Results: Our preliminary data indicates that mice immunized with aggregated/oligomerized preparations of ABri recognized heterologous amyloid structures including oligomeric Ab and PrP. ABri has no sequence homology with Ab, tau or PrP; hence, this immune response is not amino acid sequence specific but represents a preferential targeting of the pathological protein/peptide conformations shared by Ab, tau and PrP. Immunization of APP/PS1 AD Tg and the TgSwDI mice with ABri produces significant cognitive benefits in association with marked reductions in the parenchymal and vascular amyloid burdens, as well as reduced Ab oligomer levels, in the absence of any evident toxicity. Conclusions: Our results suggest that conformationally based immunomodulation targeting the pathological conformational mimicry of multiple disease associated proteins is feasible and effective.

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药物(靶点)	适应症	全球最高研发状态

AVN-211 ( 5-HT6 receptor )	精神分裂症更多	临床3期
鲁拉西酮/环丝氨酸 ( 5-HT1A receptor x 5-HT2A receptor x 5-HT7 receptor x D2 receptor x NMDA receptor x ddlA )	自杀意念更多	临床3期
AVN-322 ( 5-HT6 receptor )	认知功能障碍更多	临床2期
AVN-101 ( 5-HT6 receptor )	阿尔茨海默症更多	临床2期
AVN-492 ( 5-HT6 receptor )	阿尔茨海默症更多	临床1期