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 Lasofoxifene

Description of Lasofoxifene: Lasofoxifene (INN) (proposed tradename Fablyn) is a non-steroidal selective estrogen receptor modulator (SERM) which is under development by Pfizer for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy, and the result of an exclusive research collaboration with Ligand Pharmaceuticals (LGND). In September 2005, Pfizer received a non-approvable letter from the U.S. Food and Drug Administration regarding lasofoxifene (trade name Oporia), a selective estrogen receptor modulator for the prevention of osteoporosis.   Lasofoxifene was approved in the EU under the brand name Fablyn by the EMEA in March 2009. Lasofoxifene is a desmethyl dihydro analog of nafoxidine.   (source: http://en.wikipedia.org/wiki/Lasofoxifene).

In Jan 2009, Pfizer Inc said it has received a complete response letter from the U.S. Food and Drug Administration (FDA) asking for additional information on the company's application for lasofoxifene. The investigational compound is currently under review for the treatment of osteoporosis in postmenopausal women at increased risk of fracture. Pfizer submitted the current application for lasofoxifene on December 18, 2007. On September 8, 2008, an FDA scientific advisory panel voted 9-3 (with one abstention) that there is a population of postmenopausal women with osteoporosis in which the benefits of lasofoxifene likely outweigh the risks. FDA is not required to follow the advice of the panel.

 From: http://www.medicalnewstoday.com/articles/135923.php.

Current developer:   Ligand Pharmaceuticals and Pfizer

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16: Wang XN, Simmons HA, Salatto CT, Cosgrove PG, Thompson DD. Lasofoxifene enhances vaginal mucus formation without causing hypertrophy and increases estrogen receptor beta and androgen receptor in rats. Menopause. 2006 Jul-Aug;13(4):609-20. PubMed PMID: 16837883.

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21: Gardner M, Taylor A, Wei G, Calcagni A Jr, Duncan B, Milton A. Clinical pharmacology of multiple doses of lasofoxifene in postmenopausal women. J Clin Pharmacol. 2006 Jan;46(1):52-8. PubMed PMID: 16397284.

22: Bramson C, Ouellet D, Roman D, Randinitis E, Gardner MJ. A single-dose pharmacokinetic study of lasofoxifene in healthy volunteers and subjects with mild and moderate hepatic impairment. J Clin Pharmacol. 2006 Jan;46(1):29-36. PubMed PMID: 16397281.

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24: Roman D, Bramson C, Ouellet D, Randinitis E, Gardner M. Effect of lasofoxifene on the pharmacokinetics of digoxin in healthy postmenopausal women.  J Clin Pharmacol. 2005 Dec;45(12):1407-12. PubMed PMID: 16291716.

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27: Ke HZ, Foley GL, Simmons HA, Shen V, Thompson DD. Long-term treatment of lasofoxifene preserves bone mass and bone strength and does not adversely affect  the uterus in ovariectomized rats. Endocrinology. 2004 Apr;145(4):1996-2005. Epub 2004 Jan 15. PubMed PMID: 14726439.

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29: Ke HZ, Qi H, Chidsey-Frink KL, Crawford DT, Thompson DD. Lasofoxifene (CP-336,156) protects against the age-related changes in bone mass, bone strength, and total serum cholesterol in intact aged male rats. J Bone Miner Res. 2001 Apr;16(4):765-73. PubMed PMID: 11316005.

30: Ke HZ, Qi H, Crawford DT, Chidsey-Frink KL, Simmons HA, Thompson DD. Lasofoxifene (CP-336,156), a selective estrogen receptor modulator, prevents bone loss induced by aging and orchidectomy in the adult rat. Endocrinology. 2000 Apr;141(4):1338-44. PubMed PMID: 10746637.

31: Yang X, Reinhold AR, Rosati RL, Liu KK. Enzyme-catalyzed asymmetric deacylation for the preparation of lasofoxifene (CP-336156), a selective estrogen receptor modulator. Org Lett. 2000 Dec 14;2(25):4025-7. PubMed PMID: 11112634.

32: Rosati RL, Da Silva Jardine P, Cameron KO, Thompson DD, Ke HZ, Toler SM, Brown TA, Pan LC, Ebbinghaus CF, Reinhold AR, Elliott NC, Newhouse BN, Tjoa CM, Sweetnam PM, Cole MJ, Arriola MW, Gauthier JW, Crawford DT, Nickerson DF, Pirie CM, Qi H, Simmons HA, Tkalcevic GT. Discovery and preclinical pharmacology of a novel, potent, nonsteroidal estrogen receptor agonist/antagonist, CP-336156, a diaryltetrahydronaphthalene. J Med Chem. 1998 Jul 30;41(16):2928-31. PubMed PMID: 9685230.