MEDI 181

2-Aminobenzimidazoles as brain penetrating H₁ antagonists for the treatment of insomnia

Wilna J. Moree, wmoree@neurocrine.com¹, Timothy Coon, tcoon@neurocrine.com¹, Jinghua Yu, jyu@isisph.com², Said Zamani-Kord, skord@sbcglobal.net, Binfeng Li, bli@neurocrine.com¹, Siobhan Malany, smalany@trlusa.com³, Mark A. Santos, mark_santos@millipore.com⁴, Lisa M. Hernandez, lhernandez@neurocrine.com¹, Robert E. Petroski, rpetroski@san.rr.com⁵, Aixia Sun, aixiasun@yahoo.com⁶, Jenny Wen, jwen@neurocrine.com¹, William A. Shirley, w_a_shirley@hotmail.com⁷, Sue Sullivan, ssullivan@synteract.com⁸, Jason Haelewyn, jhaelewyn@celgene.com⁹, Margaret J. Bradbury, marg_bradbury@hotmail.com, Paul D. Crowe, pcrowehome@gmail.com, and Graham Beaton, gbeaton@neurocrine.com¹. (1) Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, (2) Isis Pharmaceuticals, Inc, Carlsbad, CA 92008, (3) Tanabe Research Laboratories U.S.A., Inc, San Diego, CA 92121, (4) Millipore Corporation, Temecula, CA 92590, (5) CalciMedica, La Jolla, CA 92037, (6) Takeda San Diego, San Diego, CA 92121, (7) Accelrys, Inc, San Diego, CA 92121, (8) Synteract, Inc, Carlsbad, CA 92011, (9) Celgene Signal Research, San Diego, CA 92121

Histamine acts upon four separate G-protein coupled receptor subtypes: H₁, H₂, H₃ and H₄. The H₁ receptors mediate allergic responses in the periphery, while centrally they mediate the effects of histamine on arousal. Brain penetrating H₁ antagonists such as Benadryl have been shown to increase sleep or drowsiness in humans and have been used for the treatment of insomnia. Unfortunately, these OTC antihistamines have shown issues including mucosal side effects due to muscarinic receptor modulation as well as daytime drowsiness and hangover effects resulting from prolonged brain exposure. In this poster we describe our approach towards the development of selective and orally active, brain-penetrating H₁ antagonists for the treatment of insomnia with a series of 2-aminobenzimidazoles.

General Poster Session
7:00 PM-9:00 PM, Sunday, August 17, 2008 Pennsylvania Convention Center -- Hall C, Poster

Division of Medicinal Chemistry

The 236th ACS National Meeting, Philadelphia, PA, August 17-21, 2008