5 research outputs found
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 Cî—»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><sub>a</sub> and thereby
dramatically change the pharmacological profile of this class of BACE1
inhibitors. The CF<sub>3</sub> 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 CF<sub>3</sub> group
was virtually inactive in vivo