title: Discovery of highly selective brain-penetrant vasopressin 1a antagonists for the potential treatment of autism via a chemogenomic and scaffold hopping approach.
abstract: From a micromolar high throughput screening hit 7, the successful complementary application of a chemogenomic approach and of a scaffold hopping exercise rapidly led to a low single digit nanomolar human vasopressin 1a (hV1a) receptor antagonist 38. Initial optimization of the mouse V1a activities delivered suitable tool compounds which demonstrated a V1a mediated central in vivo effect. This novel series was further optimized through parallel synthesis with a focus on balancing lipophilicity to achieve robust aqueous solubility while avoiding P-gp mediated efflux. These efforts led to the discovery of the highly potent and selective brain-penetrant hV1a antagonist RO5028442 (8) suitable for human clinical studies in people with autism.
authors: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors: Hasane
authors: H
authors: Ratni
authors: Mark
authors: M
authors: Rogers-Evans
authors: Caterina
authors: C
authors: Bissantz
authors: Christophe
authors: C
authors: Grundschober
authors: Jean-Luc
authors: JL
authors: Moreau
authors: Franz
authors: F
authors: Schuler
authors: Holger
authors: H
authors: Fischer
authors: Ruben
authors: R
authors: Alvarez Sanchez
authors: Patrick
authors: P
authors: Schnider
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D001321:Autistic Disorder / Q000188:drug therapy; D001921:Brain / Q000378:metabolism*; D023281:Genomics / Q000379:methods*; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011537:Pruritus / Q000139:chemically induced / Q000188:drug therapy*; D017483:Receptors, Vasopressin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000378:metabolism; D014667:Vasopressins / Q000378:metabolism*
chemical_list: C000598570:(1-benzyl-2-methylindol-3-yl)-spiro(1H-isobenzofuran-3,4'-piperidine)-1'-yl-methanone; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065092:Antidiuretic Hormone Receptor Antagonists; D007211:Indoles; D017483:Receptors, Vasopressin; D013141:Spiro Compounds; D014662:Vasoconstrictor Agents; D014667:Vasopressins; C000598571:(6-chloro-1-(2-(dimethylamino)ethyl)indol-3-yl)-spiro(1H-isobenzofuran-3,4'-piperidine)-1'-yl-methanone