Discovery, oral pharmacokinetics and in vivo efficacy of a highly selective 5-HT4 receptor agonist: clinical compound TD-2749.
Further application of our multivalent approach to drug discovery directed to 5-HT(4) receptor agonists is described. Optimization of the linker and secondary binding amine in the indazole-tropane primary binding group series, for binding affinity and functional potency at the 5-HT(4) receptor, selectivity over the 5-HT(3) receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, resulted in the identification of clinical compound TD-2749.
Theravance, Inc., 901 Gateway Blvd, South San Francisco, CA 94080, USA. dlong@theravance.com
Daniel D
DD
Long
Scott R
SR
Armstrong
David T
DT
Beattie
Seok-Ki
SK
Choi
Paul R
PR
Fatheree
Roland A L
RA
Gendron
Adam A
AA
Goldblum
Patrick P
PP
Humphrey
Daniel G
DG
Marquess
Jeng-Pyng
JP
Shaw
Jacqueline A M
JA
Smith
S
S
Derek Turner
Ross G
RG
Vickery
D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D055808:Drug Discovery; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009928:Organ Specificity; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D058828:Serotonin 5-HT4 Receptor Agonists / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
D006571:Heterocyclic Compounds; D010879:Piperazines; D058828:Serotonin 5-HT4 Receptor Agonists; C576926:TD-2749