Discovery of 4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one (4991W93), a 5HT(1B/1D) receptor partial agonist and a potent inhibitor of electrically induced plasma extravasation

K S Jandu; V Barrett; M Brockwell; D Cambridge; D R Farrant; C Foster; H Giles; R C Glen; A P Hill; H Hobbs; A Honey; G R Martin; J Salmon; D Smith; P Woollard; D L Selwood

doi:10.1021/jm000956k

Discovery of 4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one (4991W93), a 5HT(1B/1D) receptor partial agonist and a potent inhibitor of electrically induced plasma extravasation

J Med Chem. 2001 Mar 1;44(5):681-93. doi: 10.1021/jm000956k.

Authors

K S Jandu¹, V Barrett, M Brockwell, D Cambridge, D R Farrant, C Foster, H Giles, R C Glen, A P Hill, H Hobbs, A Honey, G R Martin, J Salmon, D Smith, P Woollard, D L Selwood

Affiliation

¹ GlaxoWellcome, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK.

PMID: 11262079
DOI: 10.1021/jm000956k

Abstract

Utilizing a pharmacophoric model of binding of 3-(2-aminoethyl)indoles to 5HT(1B/1D) receptors, we identified the 3-aminocyclobutyl group as a potential ethylamine isostere. A novel multidimensional chemometric approach was used to predict the intrinsic activity (degree of agonism) at the receptor. A qualitative model for pharmacokinetic properties was then used to guide the synthesis toward molecules likely to have oral bioavailability in humans. A novel synthetic route to 3-(3-dimethylaminocyclobutyl)indoles was developed. Analogues showed generally lower intrinsic activity at 5HT(1B/1D) receptors than their ethylamine counterparts. 4-[3-(trans-3-Dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one (4991W93, 1) was identified as a partial agonist against 5HT(1B/1D) receptors, with low intrinsic activity. This molecule also has significant activity against 5HT(1F) receptors but is selective over other 5HT receptors. In addition this compound was found to be an exceptionally potent inhibitor of electrically induced plasma extravasation. Compound 1 may have utility in the treatment and prophylaxis of migraine.

MeSH terms

Administration, Oral
Animals
Binding, Competitive
Biological Availability
Brain / blood supply
Brain / metabolism
CHO Cells
Capillary Permeability / drug effects*
Cattle
Cricetinae
Ear / blood supply
Electric Stimulation
Guinea Pigs
Humans
In Vitro Techniques
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / pharmacology
Male
Migraine Disorders / drug therapy
Models, Molecular
Oxazoles / chemical synthesis*
Oxazoles / chemistry
Oxazoles / pharmacology
Rabbits
Rats
Receptor, Serotonin, 5-HT1B
Receptor, Serotonin, 5-HT1D
Receptors, Serotonin / drug effects*
Receptors, Serotonin / metabolism
Regional Blood Flow / drug effects
Serotonin Receptor Agonists / chemical synthesis*
Serotonin Receptor Agonists / chemistry
Serotonin Receptor Agonists / pharmacology
Serum Albumin, Bovine / metabolism
Structure-Activity Relationship
Trigeminal Ganglion / physiology
Vasoconstrictor Agents / chemical synthesis*
Vasoconstrictor Agents / chemistry
Vasoconstrictor Agents / pharmacology

Substances

4991W93
HTR1B protein, human
Indoles
Oxazoles
Receptor, Serotonin, 5-HT1B
Receptor, Serotonin, 5-HT1D
Receptors, Serotonin
Serotonin Receptor Agonists
Vasoconstrictor Agents
Serum Albumin, Bovine