[Show abstract][Hide abstract] ABSTRACT: A series of benzoxazinones was synthesized and evaluated as novel long chain fatty acid elongase 6 (ELOVL6) inhibitors. Exploration of the SAR of the UHTS lead 1a led to the identification of (S)-1y that possesses a unique chiral quarternary center and a pyrazole ring as critical pharmacophore elements. Compound (S)-1y showed potent and selective inhibitory activity toward human ELOVL6 while displaying potent inhibitory activity toward both mouse ELOVL3 and 6 enzymes. Compound (S)-1y showed acceptable pharmacokinetic profiles after oral dosing in mice. Furthermore, (S)-1y significantly suppressed the elongation of target fatty acids in mouse liver at 30 mg/kg oral dosing.
No preview · Article · Nov 2009 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: A series of imidazo[1,2-a]pyridine derivatives was identified and evaluated for MCH1R binding and antagonistic activity. Introduction of a methyl substituent at the 3-position of imidazo[1,2-a]pyridine provided compounds with a significant improvement in MCH1R affinity. Representative compounds in this series exhibited good potency and brain exposure in rats.
[Show abstract][Hide abstract] ABSTRACT: A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.
[Show abstract][Hide abstract] ABSTRACT: ELOVL6, a member of the elongation of very long-chain fatty acids (ELOVL) family, has recently been identified as the rate-limiting
enzyme for the elongation of palmitoyl-CoA. ELOVL6 deficient mice are protected from high-fat diet induced insulin resistance,
suggesting that ELOVL6 might be a promising target for the treatment of metabolic disorders. Despite the increasing interest
in Elovl6 as a therapeutic target, the lack of chemical tools for this enzyme has limited further elucidation of the biochemical
and pharmacological properties of ELOVL6. We have identified Compound-A, a potent inhibitor for ELOVL6, by screening our company
library and subsequently optimizing hit compounds. Compound-A potently inhibited human and mouse ELOVL6 and displayed >100-fold
greater selectivity for ELOVL6 over other ELOVL family members. Consistent with its potent and selective inhibitory activity
toward ELOVL6, [3H]Compound-A bound to ELOVL6 with high affinity while showing no specific binding to other ELOVL enzymes. The observation
that [3H]Compound-A bound to ELOVL6 in a palmitoyl-CoA-dependent manner in the absence of malonyl-CoA and NADPH suggests that Compound-A
might recognize an enzyme–substrate complex, e.g. an acyl–enzyme intermediate. Collectively, these observations demonstrate
that Compound-A and its tritiated form are useful tools for biochemical and pharmacological characterization of ELOVL6.
No preview · Article · Jul 2009 · Journal of Biochemistry
[Show abstract][Hide abstract] ABSTRACT: A series of 2-aminobenzimidazole-based MCH1R antagonists was identified by core replacement of the aminoquinoline lead 1. Subsequent modification of the 2- and 5-positions led to improvement in potency and intrinsic clearance. Compound 25 exhibited good plasma and brain exposure, and attenuated MCH induced food intake at 30mg/kg PO in rats.
No preview · Article · Jun 2009 · Bioorganic & medicinal chemistry letters
[Show abstract][Hide abstract] ABSTRACT: Optimization of high-throughput screening hit 1a led to the identification of a novel spiro-piperidine class of melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. Compound 3c was identified as a highly potent and selective MCH-1R antagonist, which has an IC(50) value of 0.09 nM at hMCH-1R. The synthesis and structure-activity relationships of the novel spiro-piperidine MCH-1R antagonists are described.
No preview · Article · May 2009 · Bioorganic & medicinal chemistry letters