title: Orally active purine-based inhibitors of the heat shock protein 90.
abstract: Orally active Hsp90 inhibitors are of interest as potential chemotherapeutic agents. Recently, fully synthetic 8-benzyladenines and 8-sulfanyladenines such as 4 were disclosed as Hsp90 inhibitors, but these compounds are not water soluble and consequently have unacceptably low oral bioavailabilities. We now report that water-solubility can be achieved by inserting an amino functionality in the N(9) side chain. This results in compounds that are potent, soluble in aqueous media, and orally bioavailable. In an HER-2 degradation assay, the highest potency was achieved with the neopentylamine 42 (HER-2 IC(50) = 90 nM). In a murine tumor xenograft model (using the gastric cancer cell line N87), the H(3)PO(4) salts of the amines 38, 39, and 42 induced tumor growth inhibition when administered orally at 200 mg/kg/day. The amines 38, 39, and 42 are the first Hsp90 inhibitors shown to inhibit tumor growth upon oral dosage.
authors.affiliation: Department of Medicinal Chemistry, Conforma Therapeutics Corporation, San Diego, California 92121, USA. mbiamonte@conformacorp.com
authors.forename: Marco A
authors.initials: MA
authors.lastname: Biamonte
authors.forename: Jiandong
authors.initials: J
authors.lastname: Shi
authors.forename: Kevin
authors.initials: K
authors.lastname: Hong
authors.forename: David C
authors.initials: DC
authors.lastname: Hurst
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Junhua
authors.initials: J
authors.lastname: Fan
authors.forename: David J
authors.initials: DJ
authors.lastname: Busch
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Karjian
authors.forename: Angelica A
authors.initials: AA
authors.lastname: Maldonado
authors.forename: John L
authors.initials: JL
authors.lastname: Sensintaffar
authors.forename: Yong-Ching
authors.initials: YC
authors.lastname: Yang
authors.forename: Adeela
authors.initials: A
authors.lastname: Kamal
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Lough
authors.forename: Karen
authors.initials: K
authors.lastname: Lundgren
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Burrows
authors.forename: Gregg A
authors.initials: GA
authors.lastname: Timony
authors.forename: Marcus F
authors.initials: MF
authors.lastname: Boehm
authors.forename: Srinivas R
authors.initials: SR
authors.lastname: Kasibhatla
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: C508809:8-(2-iodo-5-methoxyphenylsulfanyl)-9-(3-isopropylaminiopropyl)-9H-purin-6-ylamine; C508810:9-(2-(2,2-dimethylpropylamino)ethyl)-8-(2-iodo-5-methoxyphenylsulfanyl)-9H-purin-6-ylamine; C508808:9-(3-sec-butylaminopropyl)-8-(2-iodo-5-methoxyphenylsulfanyl)-9H-purin-6-ylamine; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D011687:Purines; D000225:Adenine