2 research outputs found
1,2,4-Triazolo-[1,5‑<i>a</i>]pyridine HIF Prolylhydroxylase Domain‑1 (PHD-1) Inhibitors With a Novel Monodentate Binding Interaction
Herein
we describe the identification of 4-{[1,2,4]ÂtriazoloÂ[1,5-<i>a</i>]Âpyridin-5-yl}Âbenzonitrile-based inhibitors of the hypoxia-inducible
factor prolylhydroxylase domain-1 (PHD-1) enzyme. These inhibitors
were shown to possess a novel binding mode by X-ray crystallography,
in which the triazolo N1 atom coordinates in a hitherto unreported
monodentate interaction with the active site Fe<sup>2+</sup> ion,
while the benzonitrile group accepts a hydrogen-bonding interaction
from the side chain residue of Asn315. Further optimization led to
potent PHD-1 inhibitors with good physicochemical and pharmacokinetic
properties
The Discovery of Potent, Selective, and Reversible Inhibitors of the House Dust Mite Peptidase Allergen Der p 1: An Innovative Approach to the Treatment of Allergic Asthma
Blocking
the bioactivity of allergens is conceptually attractive
as a small-molecule therapy for allergic diseases but has not been
attempted previously. Group 1 allergens of house dust mites (HDM)
are meaningful targets in this quest because they are globally prevalent
and clinically important triggers of allergic asthma. Group 1 HDM
allergens are cysteine peptidases whose proteolytic activity triggers
essential steps in the allergy cascade. Using the HDM allergen Der
p 1 as an archetype for structure-based drug discovery, we have identified
a series of novel, reversible inhibitors. Potency and selectivity
were manipulated by optimizing drug interactions with enzyme binding
pockets, while variation of terminal groups conferred the physicochemical
and pharmacokinetic attributes required for inhaled delivery. Studies
in animals challenged with the gamut of HDM allergens showed an attenuation
of allergic responses by targeting just a single component, namely,
Der p 1. Our findings suggest that these inhibitors may be used as
novel therapies for allergic asthma