title: Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors  of the HCV NS3/4A protease and corresponding macrocycles.
abstract: With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties.
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Lampa
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Hiba
authors.initials: H
authors.lastname: Alogheli
authors.affiliation: Department of Chemistry-BMC, Uppsala University, BMC, Box 576, SE-751 23 Uppsala, Sweden.
authors.forename: Angelica E
authors.initials: AE
authors.lastname: Ehrenberg
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Åkerblom
authors.affiliation: Department of Pharmacy, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden; The Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Uppsala University, A Node of the Chemical Biology Consortium Sweden (CBCS), Box 580, SE-751 23 Uppsala, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Svensson
authors.affiliation: Department of Pharmacy, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden; The Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Uppsala University, A Node of the Chemical Biology Consortium Sweden (CBCS), Box 580, SE-751 23 Uppsala, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
authors.affiliation: Department of Chemistry-BMC, Uppsala University, BMC, Box 576, SE-751 23 Uppsala, Sweden.
authors.forename: U Helena
authors.initials: UH
authors.lastname: Danielson
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden. Electronic address: anja.sandstrom@orgfarm.uu.se.
authors.forename: Anja
authors.initials: A
authors.lastname: Sandström
mesh_terms: D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D002352:Carrier Proteins; D004151:Dipeptides; D047908:Intracellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D011743:Pyrimidines; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus