3 research outputs found
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