pubs.acs.org/acsmedchemlett
mitigate the likelihood of PK interactions with statins,
many of which are substrates for hepatic uptake by this
transporter.15 Furthermore, with the involvement of multi-
ple elimination mechanisms (e.g., CYP3A4 oxidation and
glucuronidation) for 22 and 23, the fraction of drug meta-
bolized via a single clearance pathway is reduced and so is
the potential for PK interactions involving that pathway.
From a drug safety perspective, no clinical signs or histological
changes were noted with 22 and 23 in subchronic toxicity
testing in rats and dogs at oral doses of 5, 50, and 500 mg/kg.
Furthermore, 22 and 23 were devoid of mutagenic re-
sponses in the Salmonella Ames assay. The necessity for
additional safety testing of metabolites17 is deemed unlikely
since no human specific metabolites were detected in in
vitro metabolism studies. On the basis of in vitro potency, in
vivo oral efficacy, safety, and favorable human disposition
attributes, compounds 22 and 23 were selected as clinical
candidates for the treatment of osteoporosis.
Paralkar, V. M.; Riccardi, K. A.; Healy, D. R.; Kalgutkar, A. S.;
Maurer, T. S.; Nguyen, H. T.; Frederick, K. S. Short-Acting 5--
(Trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one Derivatives
as Orally-Active Calcium-Sensing Receptor Antagonists. Bioorg.
Med. Chem. Lett. 2009, 19 (16), 4555–4559.
Gavai, A. V.; Vaz, R. J.; Mikkilineni, A. B.; Roberge, J. Y.; Liu, Y.;
Lawrence, R. M.; Corte, J. R.; Yang, W.; Bednarz, M.; Dickson,
J. K., Jr.; Ma, Z.; Seethala, R.; Feyen, J. H. Discovery of Novel
1-Arylmethyl Pyrrolidin-2-yl Ethanol Amines as Calcium-
Sensing Receptor Antagonists. Bioorg. Med. Chem. Lett.
2005, 15 (24), 5478–5482.
Balan, G.; Bauman, J.; Bhattacharya, S.; Castrodad, M.; Healy,
D. R.; Herr, M.; Humphries, P.; Jennings, S.; Kalgutkar, A. S.;
Kapinos, B.; Khot, V.; Lazarra, K.; Li, M.; Li, Y.; Neagu, C.;
Oliver, R.; Piotrowski, D. W.; Price, D.; Qi, H.; Simmons, H. A.;
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Marquis, R. W.; Lago, A. M.; Callahan, J. F.; Rahman, A.; Dong,
X.; Stroup, G. B.; Hoffman, S.; Gowen, M.; DelMar, E. G.; Van
Wagenen, B. C.; Logan, S.; Shimizu, S.; Fox, J.; Nemeth, E. F.;
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thyroid Hormone Secretagogues. J. Med. Chem. 2009, 52 (21),
6599–6605.
(7)
(8)
(9)
SUPPORTING INFORMATION AVAILABLE Experimental
details for the synthesis and characterization of CaSR antagonists 22
and 23 and their primary metabolites, respectively; protocols for in
vitro and in vivo pharmacology and disposition studies; and represen-
tative LC-MS/MS spectral data from metabolism studies. This material
(10) Deal, C. Potential New Drug Targets for Osteoporosis. Nature
Clin. Pract. Rheumatol. 2009, 5 (1), 20–27.
(11) Fukumoto, S.; Nakamura, T.; Nishizawa, Y.; Hayashi, M.; Matsumoto,
T. Randomized, Single-Blinded Placebo-Controlled Study of a
Novel Calcilytic, JTT-305, in Patients with Postmenopausal
Osteoporosis. ASBMR Abstract 1131.
(12) Shinagawa, Y.; Inoue, T.; Kiguchi, T.; Ikenogami, T.; Ogawa,
N.; Fukuda, K.; Nakagawa, T.; Shindo, M.; Soejima, Y. Pre-
paration of Arylcarboxylic Acid Derivatives as CaSR Antago-
nists. WO 2004/094362.
(13) Middleton, D. S.; Andrews, M.;Glossop, P.;Gymer, G.; Hepworth,
D.; Jessiman, A.; Johnson, P. S.; MacKenny, M.; Stobie, A.; Tang,
K.; Morgan, P.; Jones, B. Designing Rapid Onset Selective
Serotonin Re-uptake Inhibitors. Part 3: Site-Directed Metabolism
as a Strategy To Avoid Active Circulating Metabolites: Structure-
Activity Relationships of (Thioalkyl)phenoxy Benzyl Amines.
Bioorg. Med. Chem. Lett. 2008, 18 (19), 5303–5306.
(14) Obach, R. S. Prediction of Human Clearance of Twenty-Nine
Drugs from Hepatic Microsomal Intrinsic Clearance Data: An
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Binding to Microsomes. Drug Metab. Dispos. 1999, 27 (11),
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(15) Kalliokoski, A.; Niemi, M. Impact of OATP Transporters on
Pharmacokinetics. Br. J. Pharmacol. 2009, 158 (3), 693–705.
(16) Brown, H. C.; Ramachandran, V. Asymmetric Reduction with
Chiral Organoboranes Based on R-Pinene. Acc. Chem. Res.
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(MIST): Considerations of Mechanisms of Toxicity with Dose,
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2009, 22 (2), 267–279.
AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. Tel: 860-715-2433. Fax: 860-441-1128. E-mail: amit.
kalgutkar@pfizer.com.
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DOI: 10.1021/ml100058w ACS Med. Chem. Lett. 2010, 1, 219–223
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