An enantioselective total synthesis of the apoptosis-inducing natural product, (-)-rasfonin, is described. Camphor lactam-mediated asymmetric alkylation reactions enabled the installation of three stereogenic centers with >95:5 diastereoselectivity. A modified Corey-Peterson olefination was employed in the construction of the (E,E)-diene system. A highly diastereoselective, asymmetric vinylogous Mukaiyama aldol addition was conducted using a chiral cationic oxazaborolidine catalyst. The pyranone core of the natural product was prepared via a DBU-promoted rearrangement of a furanol to its corresponding pyranol with concomitant [1,4]-silyl transfer.
The use of cyclic α,β-unsaturated iminium-ion dienophiles is documented in two highly diastereoselective Diels-Alder (DA) reactions. The dienophilic counterion was found to have a significant effect on reactivity.
Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.
Pulmonary edema is a common ailment of heart failure patients and has remained an unmet medical need due to dose-limiting side effects associated with current treatments. Preclinical studies in rodents have suggested that inhibition of transient receptor potential vanilloid-4 (TRPV4) cation channels may offer an alternativeand potentially superiortherapy. Efforts directed toward small-molecule antagonists of the TRPV4 receptor have led to the discovery of a novel sulfone pyrrolidine sulfonamide chemotype exemplified by lead compound 6. Design elements toward the optimization of TRPV4 activity, selectivity, and pharmacokinetic properties are described. Activity of leading exemplars 19 and 27 in an in vivo model suggestive of therapeutic potential is highlighted herein.
GSK3527497,
a preclinical candidate for the inhibition of TRPV4,
was identified starting from the previously reported pyrrolidine sulfonamide
TRPV4 inhibitors 1 and 2. Optimization of
projected human dose was accomplished by specifically focusing on
in vivo pharmacokinetic parameters CLu, Vdssu, and MRT. We highlight the use of conformational changes as a novel
approach to modulate Vdssu and present results that suggest
that molecular-shape-dependent binding to tissue components governs
Vdssu in addition to bulk physicochemical properties. Optimization
of CLu within the series was guided by in vitro metabolite
identification, and the poor FaSSIF solubility imparted by the crystalline
properties of the pyrrolidine diol scaffold was improved by the introduction
of a charged moiety to enable excellent exposure from high crystalline
doses. GSK3527497 is a preclinical candidate suitable for oral and
iv administration that is projected to inhibit TRPV4 effectively in
patients from a low daily clinical dose.
The voltage-gated sodium channel
Nav1.7 continues to
be a high-profile target for the treatment of various pain afflictions
due to its strong human genetic validation. While isoform selective
molecules have been discovered and advanced into the clinic, to date,
this target has yet to bear fruit in the form of marketed therapeutics
for the treatment of pain. Lead optimization efforts over the past
decade have focused on selectivity over Nav1.5 due to its
link to cardiac side effects as well as the translation of preclinical
efficacy to man. Inhibition of Nav1.6 was recently reported
to yield potential respiratory side effects preclinically, and this
finding necessitated a modified target selectivity profile. Herein,
we report the continued optimization of a novel series of arylsulfonamide
Nav1.7 inhibitors to afford improved selectivity over Nav1.6 while maintaining rodent oral bioavailability through
the use of a novel multiparameter optimization (MPO) paradigm. We
also report in vitro–in vivo correlations from Nav1.7 electrophysiology protocols
to preclinical models of efficacy to assist in projecting clinical
doses. These efforts produced inhibitors such as compound 19 with potency against Nav1.7, selectivity over Nav1.5 and Nav1.6, and efficacy in behavioral models
of pain in rodents as well as inhibition of rhesus olfactory response
indicative of target modulation.
Investigation of a novel amino-aza-benzimidazolone structural class of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 2 (mGluR2) identified [2.2.2]-bicyclic amine 12 as an intriguing lead structure due to its promising physicochemical properties and lipophilic ligand efficiency (LLE). Further optimization led to chiral amide 18, which exhibited strong in vitro activity and attractive pharmacokinetic (PK) properties. Hypothesis-driven target design identified compound 21 as a potent, highly selective, orally bioavailable mGluR2 PAM, which addressed a CYP time-dependent inhibition (TDI) liability of 18, while maintaining excellent drug-like properties with robust in vivo activity in a clinically validated model of antipsychotic potential.
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