20 research outputs found
Diastereoselective Synthesis of β‑Heteroaryl <i>syn</i>-α-Methyl-β-Amino Acid Derivatives via a Double Chiral Auxiliary Approach
The addition of the SuperQuat enolate to five- and six-membered heterocyclic <i>tert</i>-butyl sulfinimines led to a high <i>syn</i>-selectivity of up to 99:1 in good to excellent yields. The reaction is tentatively proposed to proceed through an open-chain transition state with the presence of an α-heteroatom on the sulfinimine leading to high diastereoselectivities. The adducts were derivatized to β-amino esters and amides in a facile manner
Deuterium isotope effects in drug pharmacokinetics II: Substrate-dependence of the reaction mechanism influences outcome for cytochrome P450 cleared drugs.
Two chemotypes were examined in vitro with CYPs 3A4 and 2C19 by molecular docking, metabolic profiles, and intrinsic clearance deuterium isotope effects with specifically deuterated form to assess the potential for enhancement of pharmacokinetic parameters. The results show the complexity of deuteration as an approach for pharmacokinetic enhancement when CYP enzymes are involved in metabolic clearance. With CYP3A4 the rate limiting step was chemotype-dependent. With one chemotype no intrinsic clearance deuterium isotope effect was observed with any deuterated form, whereas with the other chemotype the rate limiting step was isotopically sensitive, and the magnitude of the intrinsic clearance isotope effect was dependent on the position(s) and extent of deuteration. Molecular docking and metabolic profiles aided in identifying sites for deuteration and predicted the possibility for metabolic switching. However, the potential for an isotope effect on the intrinsic clearance cannot be predicted and must be established by examining select deuterated versions of the chemotypes. The results show how in a deuteration strategy molecular docking, in-vitro metabolic profiles, and intrinsic clearance assessments with select deuterated versions of new chemical entities can be applied to determine the potential for pharmacokinetic enhancement in a discovery setting. They also help explain the substantial failures reported in the literature of deuterated versions of drugs to elicit a systemic enhancement on pharmacokinetic parameters
Diastereoselective Synthesis of β‑Heteroaryl <i>syn</i>-α-Methyl-β-Amino Acid Derivatives via a Double Chiral Auxiliary Approach
The addition of the SuperQuat enolate to five- and six-membered heterocyclic <i>tert</i>-butyl sulfinimines led to a high <i>syn</i>-selectivity of up to 99:1 in good to excellent yields. The reaction is tentatively proposed to proceed through an open-chain transition state with the presence of an α-heteroatom on the sulfinimine leading to high diastereoselectivities. The adducts were derivatized to β-amino esters and amides in a facile manner
A Novel Nonpeptide HIV-1 Protease Inhibitor: Elucidation of the Binding Mode and Its Application in the Design of Related Analogs
Discovery of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides as potent agonists of TGR5 via sequential combinatorial libraries
Discovery of a Series of Indazole TRPA1 Antagonists
A series
of TRPA1 antagonists is described which has as its core
structure an indazole moiety. The physical properties and <i>in vitro</i> DMPK profiles are discussed. Good <i>in vivo</i> exposure was obtained with several analogs, allowing efficacy to
be assessed in rodent models of inflammatory pain. Two compounds showed
significant activity in these models when administered either systemically
or topically. Protein chimeras were constructed to indicate compounds
from the series bound in the S5 region of the channel, and a computational
docking model was used to propose a binding mode for example compounds
Synthesis of Small 3‑Fluoro- and 3,3-Difluoropyrrolidines Using Azomethine Ylide Chemistry
Here,
we report accessing small 3-fluoropyrrolidines and 3,3-difluoropyrrolidines
through a 1,3-dipolar cycloaddition with a simple azomethine ylide
and a variety of vinyl fluorides and vinyl difluorides. We demonstrate
that vinyl fluorides within α,β-unsaturated, styrenyl
and even enol ether systems can participate in the cycloaddition reaction.
The vinyl fluorides are relatively easy to synthesize through a variety
of methods, making the 3-fluoropyrrolidines very accessible
Polyaromatic Scavenger Reagents (PAHSR): A New Methodology for Rapid Purification in Solution-Phase Combinatorial Synthesis
The discovery and optimization of benzimidazoles as selective NaV1.8 blockers for the treatment of pain
Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors
Tropomyosin receptor kinases (TrkA,
TrkB, TrkC) are activated by
hormones of the neurotrophin family: nerve growth factor (NGF), brain
derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin
4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical
proof of concept for inhibition of the TrkA kinase pathway in pain
leading to significant interest in the development of small molecule
inhibitors of TrkA. However, achieving TrkA subtype selectivity over
TrkB and TrkC via a Type I and Type II inhibitor binding mode has
proven challenging and Type III or Type IV allosteric inhibitors may
present a more promising selectivity design approach. Furthermore,
TrkA inhibitors with minimal brain availability are required to deliver
an appropriate safety profile. Herein, we describe the discovery of
a highly potent, subtype selective, peripherally restricted, efficacious,
and well-tolerated series of allosteric TrkA inhibitors that culminated
in the delivery of candidate quality compound <b>23</b>