Pharmacokinetic Studies around the Mono- and Difunctionalization of a Bioavailable Cyclic Decapeptide Scaffold.
We previously reported the design of several cyclic decapeptides based on a generic scaffold that achieved favorable oral bioavailability and exposure. With the goal to further investigate the potential of this approach, we describe herein the effect of mono- and difunctionalization of this scaffold. A series of cyclic decapeptides were therefore subjected to a range of in vitro assays and pharmacokinetic (PK) studies to investigate whether the introduction of polar or charged groups could be tolerated by the "engineered" scaffold while maintaining good PK profiles. Whereas the introduction of charged amino acids proved-besides maintaining low clearance-to conceal the inherent PK properties of the scaffold, the introduction of polar amino acids (i.e., threonine and pyridyl alanine) led to several cyclic decapeptides exhibiting excellent PK profiles together with a solubility that was significantly improved relative to that of previously reported cyclic decapeptides.
Global Discovery Chemistry/Macrocycles, Novartis Institute for BioMedical Research, Basel, 4002, Switzerland. marianne.fouche@novartis.com.
Marianne
http://orcid.org/0000-0001-6536-679X
M
Fouché
Global Discovery Chemistry/CADD, Novartis Institute for BioMedical Research, Basel, 4002, Switzerland.
Michael
M
Schäfer
Global Discovery Chemistry/Analytics (NMR), Novartis Institute for BioMedical Research, Basel, 4002, Switzerland.
Markus
M
Blatter
Metabolism and Pharmacokinetics, Novartis Institute for BioMedical Research, Basel, 4002, Switzerland.
Jörg
J
Berghausen
Metabolism and Pharmacokinetics, Novartis Institute for BioMedical Research, Basel, 4002, Switzerland.
Sandrine
S
Desrayaud
Global Discovery Chemistry/Macrocycles, Novartis Institute for BioMedical Research, Basel, 4002, Switzerland.
Hans-Jörg
HJ
Roth
D000284:Administration, Oral; D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D002463:Cell Membrane Permeability; D004285:Dogs; D006207:Half-Life; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010456:Peptides, Cyclic / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D017433:Protein Structure, Secondary; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
D000596:Amino Acids; D010456:Peptides, Cyclic
amino acids; biological activity; macrocycles; metabolism; peptides