A visible-light-driven Minisci protocol that employs an inexpensive earth-abundant metal catalyst, decacarbonyldimanganese Mn (CO) , to generate alkyl radicals from alkyl iodides has been developed. This Minisci protocol is compatible with a wide array of sensitive functional groups, including oxetanes, sugar moieties, azetidines, tert-butyl carbamates (Boc-group), cyclobutanes, and spirocycles. The robustness of this protocol is demonstrated on the late-stage functionalization of complex nitrogen-containing drugs. Photophysical and DFT studies indicate a light-initiated chain reaction mechanism propagated by Mn(CO) . The rate-limiting step is the iodine abstraction from an alkyl iodide by Mn(CO) .
In recent years, the first generation
of β-secretase (BACE1)
inhibitors advanced into clinical development for the treatment of
Alzheimer’s disease (AD). However, the alignment of drug-like
properties and selectivity remains a major challenge. Herein, we describe
the discovery of a novel class of potent, low clearance, CNS penetrant
BACE1 inhibitors represented by thioamidine 5. Further
profiling suggested that a high fraction of the metabolism (>95%)
was due to CYP2D6, increasing the potential risk for victim-based
drug–drug interactions (DDI) and variable exposure in the clinic
due to the polymorphic nature of this enzyme. To guide future design,
we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between
substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal
structures, we designed and synthesized analogues with reduced risk
for DDI, central efficacy, and improved hERG therapeutic margins.
Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimer's disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate 19 that demonstrated free brain/free plasma ≥ 1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF.
[reaction:see text] The nicotine partial agonist cytisine was prepared in five steps featuring an "in situ" Stille or Suzuki biaryl pyridine coupling. Differentiation of the pyridyl rings was accomplished via selective benzylation and then reduction of a pyridinium ring. The penultimate diazabicyclo[3.3.1]nonane intermediate was obtained with high diastereoselectivity. A similar sequence has been employed for the synthesis of novel derivative 9-methoxycytisine.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.