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1.
J Med Chem ; 64(22): 16770-16800, 2021 11 25.
Article in English | MEDLINE | ID: mdl-34704436

ABSTRACT

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. Starting from second-generation lead structures such as 2, we were able to refine these structures to obtain extremely potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules such as 44 demonstrated sufficient oral bioavailability to maintain therapeutic levels in rats and cynomolgus monkeys after dosing with an enabled formulation. We demonstrated target engagement and LDL lowering in cynomolgus monkeys essentially identical to those observed with the clinically approved, parenterally dosed antibodies. These molecules represent the first report of highly potent and orally bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles favorable for potential development as once-daily oral lipid-lowering agents. In this manuscript, we detail the design criteria and multiparameter optimization of this novel series of PCSK9 inhibitors.


Subject(s)
PCSK9 Inhibitors/pharmacology , Peptides, Cyclic/pharmacology , Administration, Oral , Animals , Biological Availability , Crystallography, X-Ray , Macaca fascicularis , Molecular Structure , PCSK9 Inhibitors/chemistry , PCSK9 Inhibitors/pharmacokinetics , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacokinetics , Rats , Structure-Activity Relationship
2.
Antimicrob Agents Chemother ; 58(3): 1294-301, 2014.
Article in English | MEDLINE | ID: mdl-24295974

ABSTRACT

Raltegravir (RAL) is a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor approved to treat HIV infection in adults in combination with other antiretrovirals. The potential of RAL to cause transporter-related drug-drug interactions (DDIs) as an inhibitor has not been well described to date. In this study, a series of in vitro experiments were conducted to assess the inhibitory effects of RAL on major human drug transporters known to be involved in clinically relevant drug interactions, including hepatic and renal uptake transporters and efflux transporters. For hepatic uptake transporters, RAL showed no inhibition of organic anion-transporting polypeptide 1B1 (OATP1B1), weak inhibition of OATP1B3 (40% inhibition at 100 µM), and no inhibition of organic cation transporter 1 (OCT1). Studies of renal uptake transporters showed that RAL inhibited organic anion transporters 1 and 3 (OAT1 and OAT3) with 50% inhibitory concentrations (IC50s) (108 µM and 18.8 µM, respectively) well above the maximum concentration of drug in plasma (Cmax) at the clinical 400-mg dose and did not inhibit organic cation transporter 2 (OCT2). As for efflux transporters, RAL did not inhibit breast cancer resistance protein (BCRP) and showed weak inhibition of multidrug and toxin extrusion protein 1 (MATE1) (52% inhibition at 100 µM) and MATE2-K (29% inhibition at 100 µM). These studies indicate that at clinically relevant exposures, RAL does not inhibit or only weakly inhibits hepatic uptake transporters OATP1B1, OATP1B3, and OCT1, renal uptake transporters OCT2, OAT1, and OAT3, as well as efflux transporters BCRP, MATE1, and MATE2-K. The propensity for RAL to cause DDIs via inhibition of these transporters is therefore considered low.


Subject(s)
HIV Integrase Inhibitors/pharmacology , Membrane Transport Proteins/drug effects , Pyrrolidinones/pharmacology , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/drug effects , Animals , Dogs , Drug Interactions , Humans , In Vitro Techniques , Liver-Specific Organic Anion Transporter 1 , Madin Darby Canine Kidney Cells , Neoplasm Proteins/drug effects , Organic Anion Transport Protein 1/drug effects , Organic Anion Transporters/drug effects , Organic Anion Transporters, Sodium-Independent/drug effects , Organic Cation Transport Proteins/drug effects , Organic Cation Transporter 1/drug effects , Organic Cation Transporter 2 , Raltegravir Potassium , Solute Carrier Organic Anion Transporter Family Member 1B3
3.
Mol Pharmacol ; 73(4): 1072-84, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18187582

ABSTRACT

Absorption of dietary cholesterol in the proximal region of the intestine is mediated by Niemann-Pick C1-like protein (NPC1L1) and is sensitive to the cholesterol absorption inhibitor ezetimibe (EZE). Although a correlation exists between EZE binding to NPC1L1 in vitro and efficacy in vivo, the precise nature of interaction(s) between NPC1L1, EZE, and cholesterol remain unclear. Here, we analyze the direct relationship between EZE analog binding to NPC1L1 and its influence on cholesterol influx in a novel in vitro system. Using the EZE analog [(3)H]AS, an assay that quantitatively measures the expression of NPC1L1 on the cell surface has been developed. It is noteworthy that whereas two cell lines (CaCo-2 and HepG2) commonly used for studying NPC1L1-dependent processes express almost undetectable levels of NPC1L1 at the cell surface, polarized Madin-Darby canine kidney (MDCKII) cells endogenously express 4 x 10(5) [(3)H]AS sites/cell under basal conditions. Depleting endogenous cholesterol with the HMG CoA reductase inhibitor lovastatin leads to a 2-fold increase in the surface expression of NPC1L1, supporting the contention that MDCKII cells respond to changes in cholesterol homeostasis by up-regulating a pathway for cholesterol influx. However, a significant increase in surface expression levels of NPC1L1 is necessary to characterize a pharmacologically sensitive, EZE-dependent pathway of cholesterol uptake in these cells. Remarkably, the affinity of EZE analogs for binding to NPC1L1 is almost identical to the IC(50) blocking cholesterol flux through NPC1L1 in MDCKII cells. From a mechanistic standpoint, these observations support the contention that EZE analogs and cholesterol share the same/overlapping binding site(s) or are tightly coupled through allosteric interactions.


Subject(s)
Azetidines/metabolism , Cholesterol/metabolism , Membrane Proteins/metabolism , Animals , Azetidines/chemistry , Caco-2 Cells , Cell Line , Cloning, Molecular , Dogs , Ezetimibe , Humans , Membrane Transport Proteins/metabolism , Reproducibility of Results , Sitosterols/metabolism , Sulfonamides/chemistry , Transfection , Tritium , beta-Lactams/metabolism
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