Abstract
The discovery of two histamine H(3) antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success in identifying these clinical candidates was the development of a compound design strategy that leveraged medicinal chemistry knowledge and traditional assays in conjunction with computational and in vitro safety tools. Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving our initial goal of identifying compounds with fully aligned oral drug attributes, "best-in-class" molecules.
MeSH terms
-
Animals
-
Blood Proteins / metabolism
-
Blood-Brain Barrier / metabolism
-
Cell Line
-
Cyclobutanes / chemical synthesis*
-
Cyclobutanes / pharmacology
-
Cyclobutanes / toxicity
-
Dogs
-
Drinking Behavior / drug effects
-
Drug Design*
-
High-Throughput Screening Assays
-
Histamine Antagonists / chemical synthesis*
-
Histamine Antagonists / pharmacology
-
Histamine Antagonists / toxicity
-
Humans
-
In Vitro Techniques
-
Kidney / metabolism
-
Lipidoses / chemically induced
-
Lipidoses / metabolism
-
Lung / metabolism
-
Microsomes, Liver / drug effects
-
Microsomes, Liver / metabolism
-
Models, Molecular
-
Molecular Structure
-
Phospholipids / metabolism
-
Protein Binding
-
Pyrrolidines / chemical synthesis*
-
Pyrrolidines / pharmacology
-
Pyrrolidines / toxicity
-
Rats
-
Rats, Sprague-Dawley
-
Receptors, Histamine H3 / metabolism*
-
Stereoisomerism
-
Structure-Activity Relationship
Substances
-
3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-N-(2-methylpropyl)cyclobutanecarboxamide
-
Blood Proteins
-
Cyclobutanes
-
Histamine Antagonists
-
N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidinylmethyl)phenyl)cyclobutanecarboxamide
-
Phospholipids
-
Pyrrolidines
-
Receptors, Histamine H3