Bioorganic & Medicinal Chemistry Letters
Metabolism-guided discovery of a potent and orally bioavailable
urea-based calcimimetic for the treatment of secondary
hyperparathyroidism
c
d
e
Paul M. Wehn a, Paul E. Harrington b, , Timothy J. Carlson , James Davis , Pierre Deprez ,
Christopher H. Fotsch b, Mark P. Grillo c, Jenny Ying-Lin Lu f, Sean Morony d, Kanaka Pattabiraman a,
Steve F. Poon b, Jeff D. Reagan f, David J. St. Jean Jr. b, Taoues Temal e, Minghan Wang d, Yuhua Yang f,
Charles Henley III d, Sarah E. Lively a
⇑
a Department of Medicinal Chemistry, Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA
b Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
c Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA
d Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
e Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France
f Department of Metabolic Disorders, Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of urea based calcimimetics was optimized for potency and oral bioavailability. Crucial to this
process was overcoming the poor pharmacokinetic properties of lead thiazole 1. Metabolism-guided
modifications, characterized by the use of metabolite identification (ID) and measurement of time depen-
dent inhibition (TDI) of CYP3A4, were essential to finding a compound suitable for oral dosing. Calcimi-
metic 18 exhibited excellent in vivo potency in a 5/6 nephrectomized rat model and cross-species
pharmacokinetics.
Received 3 September 2013
Revised 22 October 2013
Accepted 23 October 2013
Available online 31 October 2013
Keywords:
Calcimimetics
Ó 2013 Elsevier Ltd. All rights reserved.
Positive allosteric modulators
1,2,4-Thiadiazoles
Metabolite ID
Time dependent inhibition
Secondary hyperparathyroidism (secondary HPT) is a condition
characterized by the chronic elevation of parathyroid hormone
(PTH) that often develops in patients with compromised kidney
function.1 The regulation of PTH levels is governed by the cal-
cium-sensing receptor (CaSR), a class 3 G protein-coupled receptor
(GPCR) primarily expressed on the parathyroid gland.2 Increases in
serum Ca2+ concentration raise the level of activation of the CaSR
and inhibit PTH secretion, whereas decreases in serum Ca2+ concen-
tration reduce CaSR activation and enhance PTH secretion.3 Left
untreated, secondary HPT can lead to limb deformities as well as
bone and joint pain. The discovery of positive allosteric modulators
of the CaSR, type II calcimimetics, represents a novel therapy for the
treatment of secondary HPT.4 Such agents increase the sensitivity of
the CaSR to serum Ca2+ and thereby decrease secretion of PTH.
II calcimimetic with the disclosure of R-568 and related analogues.5
Subsequent work to identify new calcimimetic agents has focused
almost entirely on derivatives that retain a basic
a-methylbenzyl
amine moiety.6 A novel series of benzothiazole urea based calcim-
imetics arising from R-568 and fendiline was recently disclosed.7
Further development of this series led to 1.8 In vivo studies with
1, using a 5/6 nephrectomized rat model of kidney failure wherein
O
N
H
NHSO2Me
Ph
N
N
N
In
a groundbreaking publication, Nemeth and co-workers
1
described the in vitro and in vivo pharmacology of the first type
Ph
O
S
hCaSR EC50 = 16 nM
Rat CL = 3.8 L/h/kg
⇑
Corresponding author. Tel.: +1 805 313 5564; fax: +1 805 480 1337.
Figure 1. Thiazole 1, a urea-based calcimimetic.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.