FASGEN Inc.

Baltimore Highlands, MD, United States

FASGEN Inc.

Baltimore Highlands, MD, United States
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Outlaw V.K.,Johns Hopkins University | Wydysh E.A.,Johns Hopkins University | Vadlamudi A.,FASGEN Inc. | Medghalchi S.M.,FASGEN Inc. | Townsend C.A.,Johns Hopkins University
MedChemComm | Year: 2014

Despite a rising demand for anti-obesity therapeutics, few effective pharmacological options are clinically available that target the synthesis and accumulation of body fat. Moderate inhibition of mammalian glycerol-3-phosphate acyltransferase (GPAT) with 2-(alkanesulfonamido)benzoic acids has recently been described in vitro, accompanied by promising weight loss in vivo. In silico docking studies with 2-(octanesulfonamido)benzoic acid modeled into the active site of squash GPAT revealed an unoccupied volume lined with hydrophobic residues proximal to C-4 and C-5 of the benzoic acid ring. In an effort to produce more potent GPAT inhibitors, a series of 4- and 5-substituted analogs were designed, synthesized, and evaluated for inhibitory activity. In general, compounds containing hydrophobic substituents at the 4- and 5-positions, such as biphenyl and alkylphenyl hydrocarbons, exhibited an improved inhibitory activity against GPAT in vitro. The most active compound, 4-([1,1′- biphenyl]-4-carbonyl)-2-(octanesulfonamido)benzoic acid, demonstrated an IC 50 of 8.5 μM and represents the best GPAT inhibitor discovered to date. Conversely, further substitution with hydroxyl or fluoro groups, led to a 3-fold decrease in activity. These results are consistent with the presence of a hydrophobic pocket and may support the binding model as a potential tool for developing more potent inhibitors. © 2014 the Partner Organisations.


Wydysh E.A.,Johns Hopkins University | Vadlamudi A.,FASGEN Inc. | Medghalchi S.M.,FASGEN Inc. | Townsend C.A.,Johns Hopkins University
Bioorganic and Medicinal Chemistry | Year: 2010

Glycerol 3-phosphate acyltransferase (GPAT) isozymes are central control points for fat synthesis in mammals. Development of inhibitors of these membrane-bound enzymes could lead to an effective treatment for obesity, but is thwarted by an absence of direct structural information. Based on a highly successful study involving conformationally constrained glycerol 3-phosphate analogs functioning as potent glycerol 3-phosphate dehydrogenase inhibitors, several series of cyclic bisubstrate and transition state analogs were designed, synthesized, and tested as GPAT inhibitors. The weaker in vitro inhibitory activity of these compounds compared to a previously described benzoic acid series was then examined in docking experiments with the soluble squash chloroplast GPAT crystal structure. These in silico experiments indicate that cyclopentyl and cyclohexyl scaffolds prepared in this study may be occluded from the enzyme active site by two protein loops that sterically guard the phosphate binding region. In view of these findings, future GPAT inhibitor design will be driven toward compounds based on planar frameworks able to slide between these loops and enter the active site, resulting in improved inhibitory activity. © 2010 Elsevier Ltd. All rights reserved.


Patent
FASGEN Inc. and Johns Hopkins University | Date: 2010-01-13

A pharmaceutical composition comprising a pharmaceutical diluent and a compound of formula IV wherein R^(21)=H, C_(1)-C_(20 )alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, or alkylaryl, CH_(2)OR^(25), C(O)R^(25), CO(O)R^(25), C(O)NR^(25)R^(26), CH_(2)C(O)R^(25), or CH^(2)C(O)NHR_(25), where R_(25 )and R_(26 )are each independently H, C_(1)-C_(10 )alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, or alkylaryl, optionally containing one or more halogen atoms. R^(22)=OH, OR^(27), OCH_(2)C(O)R^(27), OCH_(2)C(O)NHR^(27), OC(O)R^(27), OC(O)OR^(27), OC(O)NHNHR^(5), or OC(O)NR^(27)R^(28), where R^(27 )and R^(28 )are each independently H, C_(1)-C_(20 )alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, or alkylaryl, and where R^(27 )and R^(28 )can each optionally contain halogen atoms; R^(23 )and R^(24), the same or different from each other, are C_(1)-C_(20 )alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, or alkylaryl. Methods of using such formulations for the treatment of cancer, to effect weight loss, to treat microbially-based infections, to inhibit neuropeptide-Y and/or fatty acid synthase, and to stimulate CPT-1.


Patent
FASGEN Inc. and Johns Hopkins University | Date: 2011-11-16

A pharmaceutical composition comprising a pharmaceutical diluent and a compound of formula IV^(21)= H, C_(1)-C_(20) alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, or alkylaryl, -CH_(2)OR^(25), -C(O)R^(25), -CO(O)R^(25), -C(O)NR^(25)R^(26), -CH_(2)C(O)R^(25), or -CH^(2)C(O)NHR_(25), where R_(25) and R_(26) are each independently H, C_(1)-C_(10) alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, or alkylaryl, optionally containing one or more halogen atoms. R^(22) = -OH, -OR^(27), -OCH_(2)C(O)R^(27), -OCH_(2)C(O)NHR^(27), -OC(O)R^(27), -OC(O)OR^(27), -OC(O)NHNH-R^(5), or -OC(O)NR^(27)R^(28), where R^(2) and R^(28) are each independently H, C_(1)-C_(20) alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, or alkylaryl, and where R^(27) and R^(28) can each optionally contain halogen atoms; R^(23) and R^(24), the same or different from each other, are C_(1)-C_(20) alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, or alkylaryl. Methods of using such formulations for the treatment of cancer, to effect weight loss, to treat microbially-based infections, to inhibit neuropeptide-Y and/or fatty acid synthase, and to stimulate CPT-1.


Patent
FASGEN Inc. and Johns Hopkins University | Date: 2011-11-16

A pharmaceutical composition comprising a pharmaceutical diluent and a compound of formula IV^(21)= H, C_(1)-C_(20) alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, or alkylaryl, -CH_(2)OR^(25), -C(O)R^(25), -CO(O)R^(25), -C(O)NR^(25)R^(26), -CH_(2)C(O)R^(25), or -CH^(2)C(O)NHR_(25), where R_(25) and R_(26) are each independently H, C_(1)-C_(10) alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, or alkylaryl, optionally containing one or more halogen atoms. R^(22) -OH, -OR^(27), -OCH_(2)C(O)R^(27), -OCH_(2)C(O)NHR^(27), -OC(O)R^(27), -OC(O)OR^(27), -OC(O)NHNH-R^(5), or -OC(O)NR^(27)R^(28), where R^(27) and R^(28) are each independently H, C_(1)-C_(20) alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, or alkylaryl, and where R^(27) and R^(28) can each optionally contain halogen atoms; R^(23) and R^(24), the same or different from each other, are C_(1)-C_(20) alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, or alkylaryl. Methods of using such formulations for the treatment of cancer, to effect weight loss, to treat microbially-based infections, to inhibit neuropeptide-Y and/or fatty acid synthase, and to stimulate CPT-1.

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