Construction of Multifunctional Modules for Drug Discovery: Synthesis of Novel Thia/Oxa-Azaspiro[3.4]octanes

New classes of thia/oxa-azaspiro[3.4]octanes are synthesized through the implementation of robust and step-economic routes. The targeted spirocycles have been designed to act as novel, multifunctional, and structurally diverse modules for drug discovery. Furthermore, enantioselective approaches to the spirocycles are reported

Synthesis of Novel Azaspiro[3.4]octanes as Multifunctional Modules in Drug Discovery

Step-economic and scalable syntheses of novel thia-azaspiro[3.4]octanes are reported. These spirocycles and some related intermediates can serve as uncharted multifunctional modules for drug discovery chemistry

Synthesis and Stability of Oxetane Analogs of Thalidomide and Lenalidomide

Oxetanes are used in drug discovery to enable physicochemical and metabolic property enhancement for the structures to which they are grafted. An imide CO to oxetane swap on thalidomide and lenalidomide templates provides analogs with similar physicochemical and <i>in vitro</i> properties of the parent drugs, with an important exception: oxetane analog <b>2</b> displays a clear differentiation with respect to human plasma stability. The prospect of limiting <i>in vivo</i> stability/metabolism, blocking <i>in vivo</i> racemization, and potentially altering teratogenicity is appealing

Discovery of Highly Selective Brain-Penetrant Vasopressin 1a Antagonists for the Potential Treatment of Autism via a Chemogenomic and Scaffold Hopping Approach

From a micromolar high throughput screening hit <b>7</b>, the successful complementary application of a chemogenomic approach and of a scaffold hopping exercise rapidly led to a low single digit nanomolar human vasopressin 1a (hV1a) receptor antagonist <b>38</b>. Initial optimization of the mouse V1a activities delivered suitable tool compounds which demonstrated a V1a mediated central <i>in vivo</i> effect. This novel series was further optimized through parallel synthesis with a focus on balancing lipophilicity to achieve robust aqueous solubility while avoiding P-gp mediated efflux. These efforts led to the discovery of the highly potent and selective brain-penetrant hV1a antagonist RO5028442 (<b>8</b>) suitable for human clinical studies in people with autism

β‑Secretase (BACE1) Inhibitors with High in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer’s Disease

An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the p<i>K</i>_a and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF₃ substituted oxazine <b>89</b>, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF Aβ40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Aβ40 and 42 even after 24 h. In contrast to <b>89</b>, compound <b>1b</b> lacking the CF₃ group was virtually inactive in vivo