title: Synthesis and evaluation of heteroarylalanine diacids as potent and selective neutral endopeptidase inhibitors.
abstract: Heteroarylalanine derivatives 4 were designed as potential inhibitors of neutral endopeptidase (NEP EC 3.4.24.11). Selectivity over other zinc metalloproteinases was explored through occupation of the S2' subsite within NEP. Structural optimisation led to the identification of 5-phenyl oxazole 4f, a potent and selective NEP inhibitor. A crystal structure of the inhibitor bound complex is reported.
authors.affiliation: Pfizer Global Research and Development, Ramsgate Road, Sandwich CT13 9NJ, UK. mel.s.glossop@pfizer.com
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Glossop
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bazin
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Dack
authors.forename: David N A
authors.initials: DN
authors.lastname: Fox
authors.forename: Graeme A
authors.initials: GA
authors.lastname: MacDonald
authors.forename: Mark
authors.initials: M
authors.lastname: Mills
authors.forename: Dafydd R
authors.initials: DR
authors.lastname: Owen
authors.forename: Chris
authors.initials: C
authors.lastname: Phillips
authors.forename: Keith A
authors.initials: KA
authors.lastname: Reeves
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Ringer
authors.forename: Ross S
authors.initials: RS
authors.lastname: Strang
authors.forename: Christine A L
authors.initials: CA
authors.lastname: Watson
mesh_terms: D000143:Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000409:Alanine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010080:Oxazoles / Q000737:chemistry* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C560919:5-phenyl oxazole; D000143:Acids; D010080:Oxazoles; D011480:Protease Inhibitors; D015260:Neprilysin; D000409:Alanine