Development of a highly selective, orally bioavailable and CNS penetrant M1 agonist derived from the MLPCN probe ML071

Evan P Lebois; Gregory J Digby; Douglas J Sheffler; Bruce J Melancon; James C Tarr; Hyekyung P Cho; Nicole R Miller; Ryan Morrison; Thomas M Bridges; Zixiu Xiang; J Scott Daniels; Michael R Wood; P Jeffrey Conn; Craig W Lindsley

doi:10.1016/j.bmcl.2011.08.084

Development of a highly selective, orally bioavailable and CNS penetrant M1 agonist derived from the MLPCN probe ML071

Bioorg Med Chem Lett. 2011 Nov 1;21(21):6451-5. doi: 10.1016/j.bmcl.2011.08.084. Epub 2011 Aug 24.

Authors

Evan P Lebois¹, Gregory J Digby, Douglas J Sheffler, Bruce J Melancon, James C Tarr, Hyekyung P Cho, Nicole R Miller, Ryan Morrison, Thomas M Bridges, Zixiu Xiang, J Scott Daniels, Michael R Wood, P Jeffrey Conn, Craig W Lindsley

Affiliation

¹ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

Abstract

Herein we report the discovery and SAR of a novel series of M(1) agonists based on the MLPCN probe, ML071. From this, VU0364572 emerged as a potent, orally bioavailable and CNS penetrant M(1) agonist with high selectivity, clean ancillary pharmacology and enantiospecific activity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Biological Availability
Cell Line
Central Nervous System / metabolism*
Humans
Muscarinic Agonists / administration & dosage*
Muscarinic Agonists / chemistry
Muscarinic Agonists / pharmacokinetics*
Rats
Receptor, Muscarinic M1 / agonists*
Structure-Activity Relationship

Substances

Muscarinic Agonists
Receptor, Muscarinic M1

Abstract

Publication types

MeSH terms

Substances

Grants and funding