BIOMAT Database Logo BIOMAT Database Logo

New spiropiperidines as potent and selective non-peptide tachykinin NK2 receptor antagonists. 1995

P W Smith, and A W Cooper, and R Bell, and I J Beresford, and P M Gore, and A B McElroy, and J M Pritchard, and V Saez, and N R Taylor, and R L Sheldrick
Department of Medicinal Chemistry, Glaxo Wellcome Medicines Research Centre, Stevenage, Herts, U.K.

The synthesis of a series of 2-(5-fluoro-1H-indol-3-yl)ethyl spiropiperidines is described together with their tachykinin NK2 receptor affinities measured in a rat colon binding assay. Equivalent NK2 receptor binding affinity was observed for the spirooxazolidinone 3-benzyl-8-[2-(5-fluoro-1H-indol-3-yl)ethyl]-1-oxa-3,8-diazaspiro[4.5] decan-2-one (3a), the imidazolidinone 3-benzyl-8-[2-(5-fluoro-1H-indol-3-yl)ethyl]-1,3,8-triazaspiro[4.5 ] decan-2-one (3s), and the pyrrolidinone 2-benzyl-8-[2-(5-fluoro-1H-indol-3-yl)ethyl]-2,8-diazaspiro[4.5]decan -3 - one (3t). Substitution in the phenyl ring of compound 3a produced no significant enhancement in NK2 binding affinity. Replacement of the phenyl ring in 3a with other aromatic rings resulted in a significant loss in binding affinity. Compound 3a was shown to be a potent NK2 receptor antagonist in guinea pig trachea where it also demonstrated 1000-fold selectivity for NK2 receptors over NK1. In the anesthetized guinea pig, compound 3a administered by the intravenous or oral route displayed potent and long-lasting antagonist activity against NK2 receptor agonist induced bronchoconstriction.

UI MeSH Term Description Entries
D007211 Indoles Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
D008968 Molecular Conformation The characteristic three-dimensional shape of a molecule. Molecular Configuration,3D Molecular Structure,Configuration, Molecular,Molecular Structure, Three Dimensional,Three Dimensional Molecular Structure,3D Molecular Structures,Configurations, Molecular,Conformation, Molecular,Conformations, Molecular,Molecular Configurations,Molecular Conformations,Molecular Structure, 3D,Molecular Structures, 3D,Structure, 3D Molecular,Structures, 3D Molecular
D010446 Peptide Fragments Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques. Peptide Fragment,Fragment, Peptide,Fragments, Peptide
D010880 Piperidines A family of hexahydropyridines.
D011817 Rabbits A burrowing plant-eating mammal with hind limbs that are longer than its fore limbs. It belongs to the family Leporidae of the order Lagomorpha, and in contrast to hares, possesses 22 instead of 24 pairs of chromosomes. Belgian Hare,New Zealand Rabbit,New Zealand Rabbits,New Zealand White Rabbit,Rabbit,Rabbit, Domestic,Chinchilla Rabbits,NZW Rabbits,New Zealand White Rabbits,Oryctolagus cuniculus,Chinchilla Rabbit,Domestic Rabbit,Domestic Rabbits,Hare, Belgian,NZW Rabbit,Rabbit, Chinchilla,Rabbit, NZW,Rabbit, New Zealand,Rabbits, Chinchilla,Rabbits, Domestic,Rabbits, NZW,Rabbits, New Zealand,Zealand Rabbit, New,Zealand Rabbits, New,cuniculus, Oryctolagus
D003106 Colon The segment of LARGE INTESTINE between the CECUM and the RECTUM. It includes the ASCENDING COLON; the TRANSVERSE COLON; the DESCENDING COLON; and the SIGMOID COLON. Appendix Epiploica,Taenia Coli,Omental Appendices,Omental Appendix,Appendices, Omental,Appendix, Omental
D006168 Guinea Pigs A common name used for the genus Cavia. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. Cavia,Cavia porcellus,Guinea Pig,Pig, Guinea,Pigs, Guinea
D006224 Cricetinae A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS. Cricetus,Hamsters,Hamster
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

Related Publications

P W Smith, and A W Cooper, and R Bell, and I J Beresford, and P M Gore, and A B McElroy, and J M Pritchard, and V Saez, and N R Taylor, and R L Sheldrick
Peptide-based tachykinin NK2 receptor antagonists.
March 1995, Medicinal research reviews,
P W Smith, and A W Cooper, and R Bell, and I J Beresford, and P M Gore, and A B McElroy, and J M Pritchard, and V Saez, and N R Taylor, and R L Sheldrick
Discovery of a new series of potent and selective linear tachykinin NK2 receptor antagonists.
October 2007, Journal of medicinal chemistry,
P W Smith, and A W Cooper, and R Bell, and I J Beresford, and P M Gore, and A B McElroy, and J M Pritchard, and V Saez, and N R Taylor, and R L Sheldrick
Biochemical and pharmacological activities of SR 144190, a new potent non-peptide tachykinin NK2 receptor antagonist.
October 1997, Neuropeptides,
P W Smith, and A W Cooper, and R Bell, and I J Beresford, and P M Gore, and A B McElroy, and J M Pritchard, and V Saez, and N R Taylor, and R L Sheldrick
GR159897, a potent non-peptide antagonist at tachykinin NK2 receptors.
January 1995, European journal of pharmacology,
P W Smith, and A W Cooper, and R Bell, and I J Beresford, and P M Gore, and A B McElroy, and J M Pritchard, and V Saez, and N R Taylor, and R L Sheldrick
Differential effects of selective tachykinin NK2 receptor antagonists in rat spinal cord.
January 1994, European journal of pharmacology,
P W Smith, and A W Cooper, and R Bell, and I J Beresford, and P M Gore, and A B McElroy, and J M Pritchard, and V Saez, and N R Taylor, and R L Sheldrick
A potent and selective non-peptide antagonist of the neurokinin A (NK2) receptor.
January 1992, Life sciences,
P W Smith, and A W Cooper, and R Bell, and I J Beresford, and P M Gore, and A B McElroy, and J M Pritchard, and V Saez, and N R Taylor, and R L Sheldrick
Competitive antagonists discriminate between NK2 tachykinin receptor subtypes.
July 1990, British journal of pharmacology,
P W Smith, and A W Cooper, and R Bell, and I J Beresford, and P M Gore, and A B McElroy, and J M Pritchard, and V Saez, and N R Taylor, and R L Sheldrick
Tachykinin NK2 receptor antagonists. A patent review (2006 - 2010).
January 2012, Expert opinion on therapeutic patents,
P W Smith, and A W Cooper, and R Bell, and I J Beresford, and P M Gore, and A B McElroy, and J M Pritchard, and V Saez, and N R Taylor, and R L Sheldrick
Rational design of high affinity tachykinin NK2 receptor antagonists.
February 1994, Bioorganic & medicinal chemistry,
P W Smith, and A W Cooper, and R Bell, and I J Beresford, and P M Gore, and A B McElroy, and J M Pritchard, and V Saez, and N R Taylor, and R L Sheldrick
Antitussive effect of SR 48968, a non-peptide tachykinin NK2 receptor antagonist.
November 1993, European journal of pharmacology,
Copied contents to your clipboard!