title: Design of oxobenzimidazoles and oxindoles as novel androgen receptor antagonists.
abstract: Oxobenzimidazoles (e.g., 1), a novel series of androgen receptor (AR) antagonists, were discovered through de novo design guided by structure-based drug design. The compounds in this series were reasonably permeable and metabolically stable, but suffered from poor solubility. The incorporation of three dimensional structural features led to improved solubility. In addition, the observation of a 'flipped' binding mode of an oxobenzimidazole analog in an AR ligand binding domain (LBD) model, led to the design and discovery of the novel oxindole series (e.g., 2) that is a potent full antagonist of AR.
authors.affiliation: Oncology Medicinal Chemistry, Pfizer PharmaTherapeutics R&D, San Diego, CA 92121, USA. alexguo01@gmail.com
authors.forename: Chuangxing
authors.initials: C
authors.lastname: Guo
authors.forename: Mason
authors.initials: M
authors.lastname: Pairish
authors.forename: Angelica
authors.initials: A
authors.lastname: Linton
authors.forename: Susan
authors.initials: S
authors.lastname: Kephart
authors.forename: Martha
authors.initials: M
authors.lastname: Ornelas
authors.forename: Asako
authors.initials: A
authors.lastname: Nagata
authors.forename: Benjamin
authors.initials: B
authors.lastname: Burke
authors.forename: Liming
authors.initials: L
authors.lastname: Dong
authors.forename: Jon
authors.initials: J
authors.lastname: Engebretsen
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Fanjul
mesh_terms: D059002:Androgen Receptor Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D011471:Prostatic Neoplasms; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D007211:Indoles; D008024:Ligands; D011944:Receptors, Androgen