'Targeted' molecular diversity: design and development of non-peptide antagonists for cholecystokinin and tachykinin receptors.
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.
Horwell
D
D
Parke-Davis Neuroscience Research Centre, Cambridge, UK.
Pritchard
M
M
Raphy
J
J
Ratcliffe
G
G
D000595:Amino Acid Sequence; D000818:Animals; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006727:Hormone Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008536:Meglumine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019151:Peptide Library; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*; D014364:Tryptophan / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D006727:Hormone Antagonists; D007211:Indoles; D008024:Ligands; D009842:Oligopeptides; C102662:PD 140548; C103563:PD 161182; D019151:Peptide Library; D011949:Receptors, Cholecystokinin; D018039:Receptors, Tachykinin; C065599:PD 134308; D010649:Phenylalanine; D008536:Meglumine; D014364:Tryptophan; C089683:PD 154075