Transient receptor potential canonical (TRPC) proteins form nonselective cation channels that play physiological roles in a wide variety of cells. Despite growing evidence supporting the therapeutic potential of TRPC6 inhibition in treating pathological cardiac and renal conditions, mechanistic understanding of TRPC6 function and modulation remains obscure. Here we report cryo-EM structures of TRPC6 in both antagonist-bound and agonist-bound states. The structures reveal two novel recognition sites for the small-molecule modulators corroborated by mutagenesis data. The antagonist binds to a cytoplasm-facing pocket formed by S1-S4 and the TRP helix, whereas the agonist wedges at the subunit interface between S6 and the pore helix. Conformational changes upon ligand binding illuminate a mechanistic rationale for understanding TRPC6 modulation. Furthermore, structural and mutagenesis analyses suggest several disease-related mutations enhance channel activity by disrupting interfacial interactions. Our results provide principles of drug action that may facilitate future design of small molecules to ameliorate TRPC6-mediated diseases.
The Ru-catalyzed intramolecular [5+2] cycloaddition of cyclopropylenynes is investigated with respect to the regio- and diastereoselectivity as well as the functional group compatibility of the reaction. Evidence for the mechanism as occurring through a ruthenacyclopentene intermediate is elucidated from 1) the study of the diastereoselectivity of the cycloaddition; 2) the effect of variation of substituents on the regioselectivity of cyclopropyl bond cleavage in 1,2-trans- and 1,2-cis-disubstituted cyclopropanes and 3) examples that clearly do not involve ruthenacyclohexene as intermediates as products still incorporate the cyclopropyl moiety. The scope and limitations of the Ru-catalyzed cycloaddition are discussed and compared with the Rh-catalyzed reaction. The potential power of this methodology towards natural product total synthesis is demonstrated by the formation of several polycyclic systems with the chosen reaction conditions and readily available cyclopropylenyne substrates.
Palladium catalyzed asymmetric allylic alkylation reaction of an amine with two equivalents of butadiene monoxide allows for the expedient synthesis of trans- and cis-2,5-dihydropyrroles. The versatility of these chiral synthons towards the synthesis of a wide variety of iminosugar natural products was demonstrated with the short and high yielding asymmetric syntheses of (+)-DMDP, and (-)-bulgecinine. In addition, the first total synthesis of (+)-broussonetine G, a potent glycosidase inhibitor, is described along with the assignment of its relative and absolute stereochemical configuration.
A series of potent hydroxyethyl amine (HEA) derived inhibitors
of β-site APP cleaving enzyme (BACE1) was optimized to address
suboptimal pharmacokinetics and poor CNS partitioning. This work identified
a series of benzodioxolane analogues that possessed improved metabolic
stability and increased oral bioavailability. Subsequent efforts focused
on improving CNS exposure by limiting susceptibility to Pgp-mediated
efflux and identified an inhibitor which demonstrated robust and sustained
reduction of CNS β-amyloid (Aβ) in Sprague–Dawley
rats following oral administration.
Transient-receptor-potential
melastatin 8 (TRPM8), the predominant
mammalian cold-temperature thermosensor, is a nonselective cation
channel expressed in a subpopulation of sensory neurons in the peripheral
nervous system, including nerve circuitry implicated in migraine pathogenesis:
the trigeminal and pterygopalatine ganglia. Genomewide association
studies have identified an association between TRPM8 and reduced risk
of migraine. This disclosure focuses on medicinal-chemistry efforts
to improve the druglike properties of initial leads, particularly
removal of CYP3A4-induction liability and improvement of pharmacokinetic
properties. A novel series of biarylmethanamide TRPM8 antagonists
was developed, and a subset of leads were evaluated in preclinical
toxicology studies to identify a clinical candidate with an acceptable
preclinical safety profile leading to clinical candidate AMG 333,
a potent and highly selective antagonist of TRPM8 that was evaluated
in human clinical trials.
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