Abstract
A drug design strategy to non-peptide small molecule antagonists of neuropeptides is described that targets the molecular diversity which exists in the 'privileged' data set of the physico-chemical properties represented by the side-chains of the 20 genetically encoded amino acids. The strategy is exemplified by the design of a selective and high affinity cholecystokinin CCK-A antagonist PD 140548, CCK-B antagonist CI-988 (formerly PD 134308) tachykinin NK-1 antagonist PD 154075 and NK-2 antagonist Cam-2291. The NK-3 antagonists, PD 157672 and the non-peptide PD 161182, were developed from an information-rich dipeptide library constructed from 256 N-protected dipeptides and 64 hydrophobic biased dipeptides.
MeSH terms
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Amino Acid Sequence
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Animals
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Drug Design*
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Drug Evaluation, Preclinical
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Hormone Antagonists / chemical synthesis
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Hormone Antagonists / chemistry
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Hormone Antagonists / pharmacology
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Humans
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Indoles / chemical synthesis
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Indoles / chemistry
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Indoles / pharmacology
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Ligands
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Meglumine / analogs & derivatives
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Meglumine / chemical synthesis
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Meglumine / chemistry
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Meglumine / pharmacology
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Molecular Structure
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Oligopeptides / chemical synthesis
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Oligopeptides / chemistry
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Oligopeptides / pharmacology
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Peptide Library
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Phenylalanine / analogs & derivatives
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Phenylalanine / chemical synthesis
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Phenylalanine / chemistry
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Phenylalanine / pharmacology
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Receptors, Cholecystokinin / antagonists & inhibitors*
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Receptors, Tachykinin / antagonists & inhibitors*
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Tryptophan / analogs & derivatives
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Tryptophan / chemical synthesis
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Tryptophan / chemistry
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Tryptophan / pharmacology
Substances
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Hormone Antagonists
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Indoles
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Ligands
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Oligopeptides
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PD 140548
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PD 161182
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Peptide Library
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Receptors, Cholecystokinin
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Receptors, Tachykinin
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PD 134308
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Phenylalanine
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Meglumine
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Tryptophan
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PD 154075