Optimization of a Tertiary Alcohol Series of Phosphodiesterase-4 (PDE4) Inhibitors:  Structure−Activity Relationship Related to PDE4 Inhibition and Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity

Abstract

A SAR study on the tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors related to 1 is described. In addition to inhibitory potency against PDE4 and the lipopolysaccharide-induced production of TNFalpha in human whole blood, the binding affinity of these compounds for the human ether-a-go-go related gene (hERG) potassium channel (an in vitro measure for the potential to cause QTc prolongation) was assessed. Four key structural moieties in the molecule were studied, and the impact of the resulting modifications in modulating these activities was evaluated. From these studies, (+)-3d (L-869,298) was identified as an optimized structure with respect to PDE4 inhibitory potency, lack of binding affinity to the hERG potassium channel, and pharmacokinetic behavior. (+)-3d exhibited good in vivo efficacy in several models of pulmonary function with a wide therapeutic index with respect to emesis and prolongation of the QTc interval.

The Synthesis of Highly Substituted Isoxazoles by Electrophilic Cyclization: An Efficient Synthesis of Valdecoxib

“…For example, compounds 21 and 23, as the pure Z-isomers, afforded the expected product with only a slight decrease in yields (entries 12 and 13) using our standard procedure, while compound 25 provided an excellent yield of 26 (entry 14). Introducing a bulky t-Bu group (27) into the alkynone provided a quantitative yield of the desired isoxazole 28 (entry 15). Compounds 29 and 31 introduce steric bulk at the ortho positions of the parent phenyl rings.…”

Phosphodiesterase 4 Inhibitors for the Treatment of Asthma and COPD

“…It binds away from the bimetallic ion center, thus rendering its insensitivity towards Mg 2+ ion with a K d of 4700 nM with the apoenzyme [28]. Over the years, several thousands of catechol-ether based PDE4 inhibitors have been synthesized including the prototypical rolipram, and the more advanced second generation compounds such as roflumilast, cilomilast and L-869,298 [29]. Studies of over 30 of their published PDE4 cocrystals revealed that they all rely on a hydrogen bonding interaction between the invariant glutamine and their common catechol-ether oxygens, and a hydrogen bond Fig.…”

Cu(I)Br‐mediated preparation of 14C‐labeled 3‐pyridineacetate derivatives and synthesis of a novel 14C‐labeled PDE‐IV inhibitor

“…11 Candidate 3 was identified as a potent, selective PDE-IV inhibitor 12 and a 14 C-labeled tracer was needed for drug metabolism studies. Thanks to the effort of Merck process research, a 13-step synthesis of 3 was developed, and the compound 4 is an advanced intermediate from the 9th step of that very …”