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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Animals
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Antidiuretic Hormone Receptor Antagonists / chemistry
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Antidiuretic Hormone Receptor Antagonists / pharmacology*
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Autistic Disorder / drug therapy
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Brain / metabolism*
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Genomics / methods*
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High-Throughput Screening Assays
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Humans
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Indoles / chemistry
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Indoles / pharmacology*
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Male
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Mice
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Molecular Structure
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Pruritus / chemically induced
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Pruritus / drug therapy*
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Receptors, Vasopressin / chemistry
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Receptors, Vasopressin / genetics
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Receptors, Vasopressin / metabolism*
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacology*
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Vasoconstrictor Agents / metabolism
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Vasopressins / metabolism*
Substances
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(1-benzyl-2-methylindol-3-yl)-spiro(1H-isobenzofuran-3,4'-piperidine)-1'-yl-methanone
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antidiuretic Hormone Receptor Antagonists
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Indoles
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Receptors, Vasopressin
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Spiro Compounds
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Vasoconstrictor Agents
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Vasopressins
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(6-chloro-1-(2-(dimethylamino)ethyl)indol-3-yl)-spiro(1H-isobenzofuran-3,4'-piperidine)-1'-yl-methanone