4 research outputs found
Synthesis of Fmoc-Protected Arylphenylalanines (Bip Derivatives) via Nonaqueous Suzuki-Miyaura Cross-Coupling Reactions
A one-step synthesis
of Fmoc-protected aryl/heteroaryl-substituted
phenylalanines (Bip derivatives) using the nonaqueous palladium-catalyzed
SuzukiâMiyaura cross-coupling (SMC) reaction of Fmoc-protected
bromo- or iodophenylalanines is reported. This protocol allows for
the direct formation of a variety of unnatural biaryl-containing amino
acids in good to excellent yield, which can be readily used in subsequent
Fmoc solid-phase peptide synthesis. The synthetic utility of this
method is also demonstrated by the SMC reaction of bromophenylalanine-containing
tripeptides
Conformationally Constrained <i>ortho-</i>Anilino Diaryl Ureas: Discovery of 1â(2-(1â˛-Neopentylspiro[indoline-3,4â˛-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, a Potent, Selective, and Bioavailable P2Y<sub>1</sub> Antagonist
Preclinical
antithrombotic efficacy and bleeding models have demonstrated
that P2Y<sub>1</sub> antagonists are efficacious as antiplatelet agents
and may offer a safety advantage over P2Y<sub>12</sub> antagonists
in terms of reduced bleeding liabilities. In this article, we describe
the structural modification of the <i>tert</i>-butyl phenoxy
portion of lead compound <b>1</b> and the subsequent discovery
of a novel series of conformationally constrained <i>ortho</i>-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted
diaryl ureas are described as potent, orally bioavailable small-molecule
P2Y<sub>1</sub> antagonists with improved activity in functional assays
and improved oral bioavailability in rats. Homology modeling and rat
PK/PD studies on benchmark compound <b>3l</b> will also be presented.
Compound <b>3l</b> was our first P2Y<sub>1</sub> antagonist
to demonstrate a robust oral antithrombotic effect with mild bleeding
liability in the rat thrombosis and hemostasis models
Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of <i>N</i>â[(1<i>R</i>)â1-(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>â[(1<i>R</i>)â1-(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