Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
Bioorg Med Chem Lett ; 25(21): 4777-4781, 2015 Nov 01.
Article in English | MEDLINE | ID: mdl-26231160

ABSTRACT

In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67 nM), and selective compound (hERG IC50=19 µM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold).


Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Migraine Disorders/drug therapy , Oxazolidinones/pharmacology , Oxazolidinones/therapeutic use , Animals , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Rats , Structure-Activity Relationship
2.
ACS Med Chem Lett ; 4(9): 863-8, 2013 Sep 12.
Article in English | MEDLINE | ID: mdl-24900761

ABSTRACT

Rational modification of the potent calcitonin gene-related peptide (CGRP) receptor antagonist MK-3207 led to a series of analogues with enhanced CNS penetrance and a convenient chemical handle for introduction of a radiolabel. A number of (11)C-tracers were synthesized and evaluated in vivo, leading to the identification of [(11)C]8 ([(11)C]MK-4232), the first positron emission tomography tracer for the CGRP receptor.

3.
Bioorg Med Chem Lett ; 22(12): 3941-5, 2012 Jun 15.
Article in English | MEDLINE | ID: mdl-22607672

ABSTRACT

Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.


Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists , Migraine Disorders/drug therapy , Pyridines/chemical synthesis , Pyridines/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Administration, Oral , Analgesics/blood , Animals , Biological Availability , Disease Models, Animal , Dogs , Humans , Macaca mulatta , Mice , Pyridines/blood , Rats , Receptors, Calcitonin Gene-Related Peptide/metabolism , Species Specificity , Spiro Compounds/blood
SELECTION OF CITATIONS
SEARCH DETAIL
...