title: Cis-amide isosteric replacement in thienobenzoxepin inhibitors of PI3-kinase.
abstract: Substructural class effects surrounding replacement of a 'cis' N-methyl aniline amide within potent and selective thienobenzoxepin PI3-kinase inhibitors are disclosed. While a simple aryl to alkyl switch was not tolerated due to differences in preferred amide conformation, heterocyclic amide isosteres with maintained aryl substitution improved potency and metabolic stability at the cost of physical properties. These gains in potency allowed lipophilic deconstruction of the arene to simple branched alkyl substituents. As such, overall lipophilicity-neutral, MW decreases were realized relative to the aniline amide series. The improved properties for lead compound 21 resulted in high permeability, solubility and bioavailability.
authors.affiliation: Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. stevents@gene.com
authors.forename: Steven T
authors.initials: ST
authors.lastname: Staben
authors.forename: Nicole
authors.initials: N
authors.lastname: Blaquiere
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Kolesnikov
authors.forename: Steven
authors.initials: S
authors.lastname: Do
authors.forename: Erin K
authors.initials: EK
authors.lastname: Bradley
authors.forename: Jenna
authors.initials: J
authors.lastname: Dotson
authors.forename: Richard
authors.initials: R
authors.lastname: Goldsmith
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffron
authors.forename: John
authors.initials: J
authors.lastname: Lesnick
authors.forename: Cristina
authors.initials: C
authors.lastname: Lewis
authors.forename: Jeremy
authors.initials: J
authors.lastname: Murray
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.forename: Alan G
authors.initials: AG
authors.lastname: Olivero
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.forename: Lionel
authors.initials: L
authors.lastname: Rouge
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: BinQing
authors.initials: B
authors.lastname: Wei
authors.forename: Christian
authors.initials: C
authors.lastname: Wiesmann
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D052160:Benzothiazoles / Q000737:chemistry; D001584:Benzoxepins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C442855:7-methyl-6-(3-methyl-2,3-dihydro-1,3-benzothiazol-2-ylidenmethyl)(1,3)dioxolo(4',5':4,5)benzo(d)(1,3)thiazolium methylmethosulfate; D000577:Amides; D052160:Benzothiazoles; D001584:Benzoxepins; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013876:Thiophenes