title: Design and synthesis of P1-P3 macrocyclic tertiary-alcohol-comprising HIV-1 protease inhibitors.
abstract: To study P1-P3 macrocyclizations of previously reported tertiary-alcohol-comprising HIV-1 protease inhibitors (PIs), three new 14- and 15-member macrocyclic PIs were designed, synthesized by ring-closing metathesis, and evaluated alongside with 10 novel linear PIs. Cocrystallized complexes of the macrocyclic PIs and the HIV-1 protease are presented, analyzed, and discussed. The macrocyclic structures exhibited higher activities than the linear precursors with Ki and EC50 values down to 3.1 nM and 0.37 μM, respectively.
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University , P.O. Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Advait
authors.initials: A
authors.lastname: Joshi
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Véron
authors.forename: Johan
authors.initials: J
authors.lastname: Unge
authors.forename: Åsa
authors.initials: Å
authors.lastname: Rosenquist
authors.forename: Hans
authors.initials: H
authors.lastname: Wallberg
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.forename: Mats
authors.initials: M
authors.lastname: Larhed
mesh_terms: D000438:Alcohols / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D000438:Alcohols; D017320:HIV Protease Inhibitors; D047028:Macrocyclic Compounds; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1