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1.
J Med Chem ; 63(4): 1660-1670, 2020 02 27.
Article in English | MEDLINE | ID: mdl-31990537

ABSTRACT

Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound 12. Compound 12 was evaluated in a mouse pharmacodynamics (PD) model and demonstrated a 56% increase in plasma HDL-C. In a mouse reverse cholesterol transport study, compound 12 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.


Subject(s)
Cholesterol, HDL/metabolism , Enzyme Inhibitors/pharmacology , Ketones/pharmacology , Lipase/antagonists & inhibitors , Oxadiazoles/pharmacology , Animals , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Ketones/chemical synthesis , Ketones/pharmacokinetics , Male , Mice, Inbred C57BL , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacokinetics , Structure-Activity Relationship
2.
ACS Med Chem Lett ; 10(6): 911-916, 2019 Jun 13.
Article in English | MEDLINE | ID: mdl-31223447

ABSTRACT

Lead optimization of the diphenylpyridylethanamine (DPPE) and triphenylethanamine (TPE) series of CETP inhibitors to improve their pharmaceutical profile is described. Polar groups at the N-terminus position in the DPPE series resulted in further improvement in potency and pharmaceutical properties concomitant with retaining the safety, efficacy, and pharmacokinetic (PK) profile. A structure-activity relationship observed in the DPPE series was extended to the corresponding analogs in the more potent TPE series, and further optimization resulted in the identification of 2-amino-N-((R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanamide (13). Compound 13 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemetry rats, had an excellent PK profile, and demonstrated robust efficacy in human CETP/apo-B-100 dual transgenic mice and in hamsters.

3.
ACS Med Chem Lett ; 9(7): 673-678, 2018 Jul 12.
Article in English | MEDLINE | ID: mdl-30034599

ABSTRACT

Screening of a small set of nonselective lipase inhibitors against endothelial lipase (EL) identified a potent and reversible inhibitor, N-(3-(3,4-dichlorophenyl)propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (5; EL IC50 = 61 nM, ELHDL IC50 = 454 nM). Deck mining identified a related hit, N-(3-(3,4-dichlorophenyl)propyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (6a; EL IC50 = 41 nM, ELHDL IC50 = 1760 nM). Both compounds were selective against lipoprotein lipase (LPL) but nonselective versus hepatic lipase (HL). Optimization of compound 6a for EL inhibition using HDL as substrate led to N-(4-(3,4-dichlorophenyl)butan-2-yl)-1-ethyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (7c; EL IC50 = 148 nM, ELHDL IC50 = 218 nM) having improved PK over compound 6a, providing a tool molecule to test for the ability to increase HDL-cholesterol (HDL-C) levels in vivo using a reversible EL inhibitor. Compound 7c 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.

4.
Bioorg Med Chem Lett ; 26(14): 3278-3281, 2016 07 15.
Article in English | MEDLINE | ID: mdl-27256912

ABSTRACT

Hydroxyl 1,2-diphenylethanamine analogs were identified as potent inhibitors of cholesterol ester transfer protein (CETP), a therapeutic target to raise HDL cholesterol. In an effort to improve the pharmaceutical properties in the previously disclosed DiPhenylPyridineEthanamine (DPPE) series, polar groups were introduced to the N-linked quaternary center. Optimization of analogues for potency, in vitro liability profile and efficacy led to identification of lead compound 16 which demonstrated robust pharmacodynamic effects in human CETP/apo-B100 dual transgenic mice.


Subject(s)
Amines/pharmacology , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Drug Discovery , Amines/chemical synthesis , Amines/chemistry , Animals , Cholesterol Ester Transfer Proteins/metabolism , Dose-Response Relationship, Drug , Humans , Mice , Mice, Transgenic , Molecular Structure , Structure-Activity Relationship
5.
J Med Chem ; 58(22): 9010-26, 2015 Nov 25.
Article in English | MEDLINE | ID: mdl-26524347

ABSTRACT

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 10g 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 (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.


Subject(s)
Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Benzylamines/chemical synthesis , Benzylamines/pharmacology , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Animals , Anticholesteremic Agents/pharmacokinetics , Atherosclerosis/drug therapy , Benzamides/pharmacokinetics , Benzylamines/pharmacokinetics , Blood Pressure/drug effects , Cell Line , Cholesterol/metabolism , Cholesterol, HDL/blood , Cricetinae , Cytochrome P-450 CYP11B2/antagonists & inhibitors , Dogs , Drug Discovery , Humans , Macaca fascicularis , Male , Mesocricetus , Mice , Mice, Transgenic , Motor Activity/drug effects , Quinolines/pharmacology , Rats , Rats, Sprague-Dawley
8.
J Med Chem ; 55(13): 6162-75, 2012 Jul 12.
Article in English | MEDLINE | ID: mdl-22650305

ABSTRACT

A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.


Subject(s)
Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Stilbenes/chemistry , Stilbenes/pharmacology , Animals , Anticholesteremic Agents/chemical synthesis , Apolipoprotein B-100/antagonists & inhibitors , Apolipoprotein B-100/metabolism , Blood Pressure/drug effects , Cholesterol Ester Transfer Proteins/metabolism , Coronary Disease/drug therapy , Cricetinae , Drug Discovery , Heart Rate/drug effects , Humans , Inhibitory Concentration 50 , Male , Mice , Mice, Transgenic , Molecular Structure , Pyridines/chemical synthesis , Rats , Stilbenes/chemical synthesis
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