The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists.
A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit.
Johnson
Dale J
DJ
GlaxoSmithKline, New Frontiers Science Park, 3rd Avenue, Harlow, Essex CM19 5AW, UK. dalejames.johnson@gmail.com
Forbes
Ian T
IT
Watson
Steve P
SP
Garzya
Vincenzo
V
Stevenson
Graeme I
GI
Walker
Graham R
GR
Mudhar
Harminder S
HS
Flynn
Sean T
ST
Wyman
Paul A
PA
Smith
Paul W
PW
Murkitt
Graham S
GS
Lucas
Adam J
AJ
Mookherjee
Claudette R
CR
Watson
Jeannette M
JM
Gartlon
Jane E
JE
Bradford
Andrea M
AM
Brown
Fiona
F
D000818:Animals; D001583:Benzoxazoles / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008569:Memory Disorders / Q000188:drug therapy*; D018721:Muscarinic Agonists / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018697:Nootropic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000078183:Oxindoles; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*
D001583:Benzoxazoles; D007211:Indoles; D018721:Muscarinic Agonists; D018697:Nootropic Agents; D000078183:Oxindoles; D043643:Receptor, Muscarinic M1; C022960:2-oxindole; C017057:benzoxazolone