17 research outputs found
Structure-Based Design of Macrocyclic Coagulation Factor VIIa Inhibitors
On the basis of a crystal structure
of a phenylpyrrolidine lead and subsequent molecular modeling results,
we designed and synthesized a novel series of macrocyclic FVIIa inhibitors.
The optimal 16-membered macrocycle was 60-fold more potent than an
acyclic analog. Further potency optimization by incorporation of P1′
alkyl sulfone and P2 methyl groups provided a macrocycle with TF/FVIIa <i>K</i><sub>i</sub> = 1.6 nM, excellent selectivity against a
panel of seven serine proteases, and FVII-deficient prothrombin time
EC<sub>2<i>x</i></sub> = 1.2 μM. Discovery of this
potent, selective macrocyclic scaffold opens new possibilities for
the development of orally bioavailable FVIIa inhibitors
Atropisomer Control in Macrocyclic Factor VIIa Inhibitors
Incorporation of a methyl group onto
a macrocyclic FVIIa inhibitor
improves potency 10-fold but is accompanied by atropisomerism due
to restricted bond rotation in the macrocyclic structure, as demonstrated
by NMR studies. We designed a conformational constraint favoring the
desired atropisomer in which this methyl group interacts with the
S2 pocket of FVIIa. A macrocyclic inhibitor incorporating this constraint
was prepared and demonstrated by NMR to reside predominantly in the
desired conformation. This modification improved potency 180-fold
relative to the unsubstituted, racemic macrocycle and improved selectivity.
An X-ray crystal structure of a closely related analogue in the FVIIa
active site was obtained and matches the NMR and modeled conformations,
confirming that this conformational constraint does indeed direct
the methyl group into the S2 pocket as designed. The resulting rationally
designed, conformationally stable template enables further optimization
of these macrocyclic inhibitors
Design and Synthesis of Novel Meta-Linked Phenylglycine Macrocyclic FVIIa Inhibitors
Two
novel series of meta-linked phenylglycine-based macrocyclic
FVIIa inhibitors have been designed to improve the rodent metabolic
stability and PK observed with the precursor para-linked phenylglycine
macrocycles. Through iterative structure-based design and optimization,
the TF/FVIIa <i>K</i><sub>i</sub> was improved to subnanomolar
levels with good clotting activity, metabolic stability, and permeability
Discovery of Phenylglycine Lactams as Potent Neutral Factor VIIa Inhibitors
Inhibitors of Factor
VIIa (FVIIa), a serine protease in the clotting
cascade, have shown strong antithrombotic efficacy in preclinical
thrombosis models with minimal bleeding liabilities. Discovery of
potent, orally active FVIIa inhibitors has been largely unsuccessful
because known chemotypes have required a highly basic group in the
S1 binding pocket for high affinity. A recently reported fragment
screening effort resulted in the discovery of a neutral heterocycle,
7-chloro-3,4-dihydroisoquinolin-1Â(2<i>H</i>)-one, that binds
in the S1 pocket of FVIIa and can be incorporated into a phenylglycine
FVIIa inhibitor. Optimization of this P1 binding group led to the
first series of neutral, permeable FVIIa inhibitors with low nanomolar
potency
Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa–Tissue Factor Complex
Inhibitors of the tissue factor (TF)/factor
VIIa complex (TF-FVIIa)
are promising novel anticoagulants which show excellent efficacy and
minimal bleeding in preclinical models. Starting with an aminoisoquinoline
P1-based macrocyclic inhibitor, optimization of the P′ groups
led to a series of highly potent and selective TF-FVIIa inhibitors
which displayed poor permeability. Fluorination of the aminoisoquinoline
reduced the basicity of the P1 group and significantly improved permeability.
The resulting lead compound was highly potent, selective, and achieved
good pharmacokinetics in dogs with oral dosing. Moreover, it demonstrated
robust antithrombotic activity in a rabbit model of arterial thrombosis
Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors
Inhibitors
of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising
novel anticoagulants that show excellent efficacy and minimal bleeding
in preclinical models. On the basis of a zwitterionic phenylglycine
acylsulfonamide <b>1</b>, a phenylglycine benzylamide <b>2</b> was shown to possess improved permeability and oral bioavailability.
Optimization of the benzylamide, guided by X-ray crystallography,
led to a potent TF-FVIIa inhibitor <b>18i</b> with promising
oral bioavailability, but promiscuous activity in an in vitro safety
panel of receptors and enzymes. Introducing an acid on the pyrrolidine
ring, guided by molecular modeling, resulted in highly potent, selective,
and efficacious TF-FVIIa inhibitors with clean in vitro safety profile.
The pyrrolidine acid <b>20</b> showed a moderate clearance,
low volume of distribution, and a short <i>t</i><sub>1/2</sub> in dog PK studies
Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker
A novel series of macrocyclic FXIa
inhibitors was designed based
on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles,
which were double-digit nanomolar FXIa inhibitors, were further optimized
with assistance from utilization of structure-based drug design and
ligand bound X-ray crystal structures. This effort resulted in the
discovery of a macrocyclic amide linker which was found to form a
key hydrogen bond with the carbonyl of Leu41 in the FXIa active site,
resulting in potent FXIa inhibitors. The macrocyclic FXIa series,
exemplified by compound <b>16</b>, had a FXIa <i>K</i><sub>i</sub> = 0.16 nM with potent anticoagulant activity in an in
vitro clotting assay (aPTT EC<sub>1.5x</sub> = 0.27 μM) and
excellent selectivity against the relevant blood coagulation enzymes
Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis
PAR4
is a promising antithrombotic target with potential for separation
of efficacy from bleeding risk relative to current antiplatelet therapies.
In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based
HTS hit 3 with low μM potency was identified. Optimization
of the HTS hit through the use of positional SAR scanning and the
design of conformationally constrained cores led to the discovery
of a quinoxaline-benzothiazole series as potent and selective PAR4
antagonists. The lead compound 48, possessing a 2 nM
IC50 against PAR4 activation by γ-thrombin in platelet-rich
plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated
robust antithrombotic efficacy and minimal bleeding in the cynomolgus
monkey models
Tetrahydroquinoline Derivatives as Potent and Selective Factor XIa Inhibitors
Antithrombotic
agents that are inhibitors of factor XIa (FXIa)
have the potential to demonstrate robust efficacy with a low bleeding
risk profile. Herein, we describe a series of tetrahydroquinoline
(THQ) derivatives as FXIa inhibitors. Compound <b>1</b> was
identified as a potent and selective tool compound for proof of concept
studies. It exhibited excellent antithrombotic efficacy in rabbit
thrombosis models and did not prolong bleeding times. This demonstrates
proof of concept for the FXIa mechanism in animal models with a reversible,
small molecule inhibitor
Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis
PAR4
is a promising antithrombotic target with potential for separation
of efficacy from bleeding risk relative to current antiplatelet therapies.
In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based
HTS hit 3 with low μM potency was identified. Optimization
of the HTS hit through the use of positional SAR scanning and the
design of conformationally constrained cores led to the discovery
of a quinoxaline-benzothiazole series as potent and selective PAR4
antagonists. The lead compound 48, possessing a 2 nM
IC50 against PAR4 activation by γ-thrombin in platelet-rich
plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated
robust antithrombotic efficacy and minimal bleeding in the cynomolgus
monkey models