1-Alkyl-4-phenyl-6-alkoxy-1H-quinazolin-2-ones: a novel series of potent calcium-sensing receptor antagonists.
Parathyroid hormone (PTH) is an effective bone anabolic agent. However, only when administered by daily sc injections exposure of short duration is achieved, a prerequisite for an anabolic response. Instead of applying exogenous PTH, mobilization of endogenous stores of the hormone can be envisaged. The secretion of PTH stored in the parathyroid glands is mediated by a calcium sensing receptor (CaSR) a GPCR localized at the cell surface. Antagonists of CaSR (calcilytics) mimic a state of hypocalcaemia and stimulate PTH release to the bloodstream. Screening of the internal compound collection for inhibition of CaSR signaling function afforded 2a. In vitro potency could be improved >1000 fold by optimization of its chemical structure. The binding mode of our compounds was predicted based on molecular modeling and confirmed by testing with mutated receptors. While the compounds readily induced PTH release after iv application a special formulation was needed for oral activity. The required profile was achieved by using microemulsions. Excellent PK/PD correlation was found in rats and dogs. High levels of PTH were reached in plasma within minutes which reverted to baseline in about 1-2 h in both species.
Widler
Leo
L
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. leo.widler@novartis.com
Altmann
Eva
E
Beerli
René
R
Breitenstein
Werner
W
Bouhelal
Rochdi
R
Buhl
Thomas
T
Gamse
Rainer
R
Gerspacher
Marc
M
Halleux
Christine
C
John
Markus R
MR
Lehmann
Hansjoerg
H
Kalb
Oskar
O
Kneissel
Michaela
M
Missbach
Martin
M
Müller
Irene R
IR
Reidemeister
Sibylle
S
Renaud
Johanne
J
Taillardat
Agnes
A
Tommasi
Ruben
R
Weiler
Sven
S
Wolf
Romain M
RM
Seuwen
Klaus
K
D000284:Administration, Oral; D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D004285:Dogs; D020128:Inhibitory Concentration 50; D008297:Male; D010281:Parathyroid Hormone / Q000378:metabolism*; D052999:Quinazolinones / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
D050071:Bone Density Conservation Agents; D010281:Parathyroid Hormone; D052999:Quinazolinones; D044169:Receptors, Calcium-Sensing