United States Patent Application 20020120137
Kind Code A1
Houze, Jonathan ; et al. August 29, 2002
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FXR modulators
Abstract
The present invention provides compounds, pharmaceutical compositions and methods that are useful in modulating the farnesoid X receptor (FXR). As FXR is involved in negatively controlling the expression level of cholesterol 7.alpha.-hydroxylase (cyp7a), the rate-limiting enzyme involved in the oxidative metabolism of cholesterol into bile acids, the compounds described herein find utility in treating diseases associated with abnormally high or low cholesterol levels. In certain aspects, the FXR modulators (e.g., antagonists) described herein block the negative feed-back downregulation of cyp7a expression produced by certain cholic acids, the endogenous ligands for FXR. Moreover, as FXR forms heterodimers with the retinoid X receptor (RXR) in some cell types, modulation of the level of FXR activity in cells has a wide range of effects on a variety of biological processes which are mediated by RXR or other RXR-interacting proteins such as PPAR.gamma. and PPAR.alpha.. Thus, compounds described herein are useful in treating other biological activities such as obesity, diabetes, lipid associated disorders, cancer, inflammatory disorders, disorders involving a disrupted or dysfunctional epidermal barrier, and various other metabolic disorders.
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Inventors: Houze, Jonathan; (San Mateo, CA) ; McKendry, Sharon; (San Francisco, CA) ; Gergely, Joshua P.; (San Francisco, CA) ; Xia, Yi; (South San Francisco, CA) ; Shan, Bei; (Redwood City, CA) ; Kayser, Frank; (San Francisco, CA)
Correspondence Name and Address: TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
Assignee Name and Adress: Tularik Inc.
South San Francisco
CA
Serial No.: 945293
Series Code: 09
Filed: August 31, 2001
U.S. Current Class: 540/589; 546/314; 564/156
U.S. Class at Publication: 540/589; 546/314; 564/156
Intern'l Class: C07D 43/02; C07D 213/81
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Claims
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What is claimed is:
1. A compound of the formulaB.sup.1--L.sup.1--A.sup.1--L.sup.2--B.sup.2 Iwherein: A.sup.1 is a member selected from the group consisting of alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heteroarylene, heterocycloalkylene, and heterocycloalkenylene, or, alternatively, A.sup.1 represents a single or double bond linking L.sup.1 and L.sup.2; L.sup.1 and L.sup.2 are each independently a member selected from the group consisting of O--, --S--, --N(R.sup.1)--, --C(O)--, --C(O)N(R.sup.1)--, --O-alkylene-, --S-alkylene-, --N(R.sup.1)-alkylene, --C(O)-alkylene, --C(O)N(R.sup.1)-alkylene, --C(O)--O-alkylene, alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heteroarylene, heterocycloalkylene, and heterocycloalkenylene; B.sup.1 and B.sup.2 are each independently a member selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl; alternatively, L.sup.1 can be additionally linked to B.sup.1 via a group X.sup.1 to form a 5-9 member ring; and L.sup.2 can be additionally linked to B.sup.2 via a group X.sup.2 to form a 5-9 member ring; X.sup.1 and X.sup.2 are each independently a member selected from the group consisting of --O--, --S--, --N(R.sup.2)--, --C(O)--, --C(O)N(R.sup.2)--, --O-alkylene, --S-alkylene, --N(R.sup.2)-alkylene, --C(O)-alkylene, --C(O)N(R.sup.2)-alkylene, and --C(O)--O-alkylene; and R.sup.1 and R.sup.2 are each independently a member selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, aryl(heteroalkyl), (heteroaryl)alkyl, and (heteroaryl)heteroalkyl.
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