6 research outputs found
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
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
PK/PD Disconnect Observed with a Reversible Endothelial Lipase Inhibitor
Screening of a small set of nonselective
lipase inhibitors against
endothelial lipase (EL) identified a potent and reversible inhibitor, <i>N</i>-(3-(3,4-dichlorophenyl)Âpropyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide
(<b>5</b>; EL IC<sub>50</sub> = 61 nM, EL<sub>HDL</sub> IC<sub>50</sub> = 454 nM). Deck mining identified a related hit, <i>N</i>-(3-(3,4-dichlorophenyl)Âpropyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1<i>H</i>-pyrrole-3-carboxamide (<b>6a</b>; EL IC<sub>50</sub> = 41 nM, EL<sub>HDL</sub> IC<sub>50</sub> = 1760 nM). Both compounds
were selective against lipoprotein lipase (LPL) but nonselective versus
hepatic lipase (HL). Optimization of compound <b>6a</b> for
EL inhibition using HDL as substrate led to <i>N</i>-(4-(3,4<b>-</b>dichlorophenyl)Âbutan-2-yl)-1-ethyl-4-hydroxy-5-oxo-2,5-dihydro-1<i>H</i>-pyrrole-3-carboxamide (<b>7c</b>; EL IC<sub>50</sub> = 148 nM, EL<sub>HDL</sub> IC<sub>50</sub> = 218 nM) having improved
PK over compound <b>6a</b>, providing a tool molecule to test
for the ability to increase HDL-cholesterol (HDL-C) levels in vivo
using a reversible EL inhibitor. Compound <b>7c</b> did not
increase HDL-C in vivo despite achieving plasma exposures targeted
on the basis of enzyme activity and protein binding demonstrating
the need to develop more physiologically relevant in vitro assays
to guide compound progression for in vivo evaluation
Diphenylpyridylethanamine (DPPE) Derivatives as Cholesteryl Ester Transfer Protein (CETP) Inhibitors
A series of diphenylpyridylethanamine (DPPE) derivatives
was identified exhibiting potent CETP inhibition. Replacing the labile
ester functionality in the initial lead <b>7</b> generated a
series of amides and ureas. Further optimization of the DPPE series
for potency resulted in the discovery of cyclopentylurea <b>15d</b>, which demonstrated a reduction in cholesterol ester transfer activity
(48% of predose level) in hCETP/apoB-100 dual transgenic mice. The
PK profile of <b>15d</b> was suboptimal, and further optimization
of the N-terminus resulted in the discovery of amide <b>20</b> with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100
mice and in hamsters. Compound <b>20</b> demonstrated no significant
changes in either mean arterial blood pressure or heart rate in telemeterized
rats despite sustained high exposures
Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of <i>N</i>‑[(1<i>R</i>)‑1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)Âphenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)Âbenzamide (BMS-795311)
Cholesteryl ester transfer protein
(CETP) inhibitors raise HDL-C
in animals and humans and may be antiatherosclerotic by enhancing
reverse cholesterol transport (RCT). In this article, we describe
the lead optimization efforts resulting in the discovery of a series
of triphenylethanamine (TPE) ureas and amides as potent and orally
available CETP inhibitors. Compound <b>10g</b> is a potent CETP
inhibitor that maximally inhibited cholesteryl ester (CE) transfer
activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic
mice and increased HDL cholesterol content and size comparable to
torcetrapib (<b>1</b>) in moderately-fat fed hamsters. In contrast
to the off-target liabilities with <b>1</b>, no blood pressure
increase was observed with <b>10g</b> in rat telemetry studies
and no increase of aldosterone synthase (CYP11B2) was detected in
H295R cells. On the basis of its preclinical profile, compound <b>10g</b> was advanced into preclinical safety studies
Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of <i>N</i>‑[(1<i>R</i>)‑1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)Âphenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)Âbenzamide (BMS-795311)
Cholesteryl ester transfer protein
(CETP) inhibitors raise HDL-C
in animals and humans and may be antiatherosclerotic by enhancing
reverse cholesterol transport (RCT). In this article, we describe
the lead optimization efforts resulting in the discovery of a series
of triphenylethanamine (TPE) ureas and amides as potent and orally
available CETP inhibitors. Compound <b>10g</b> is a potent CETP
inhibitor that maximally inhibited cholesteryl ester (CE) transfer
activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic
mice and increased HDL cholesterol content and size comparable to
torcetrapib (<b>1</b>) in moderately-fat fed hamsters. In contrast
to the off-target liabilities with <b>1</b>, no blood pressure
increase was observed with <b>10g</b> in rat telemetry studies
and no increase of aldosterone synthase (CYP11B2) was detected in
H295R cells. On the basis of its preclinical profile, compound <b>10g</b> was advanced into preclinical safety studies