Bruce A. Dressman

Use of solid supported nucleophiles and electrophiles for the purification of non-peptide small molecule libraries

Abstract Solid supported nucleophiles and electrophiles are employed to expedite the work-up and purification of a variety of amine alkylations acylacylations. These solid suported scavengers are particularly advantageous for the construction of non-peptide libraries in a parallel array format.

Rapid purification of small molecule libraries by ion exchange chromatography

Abstract Amines and acylated amines are synthesized in traditional solution phase reactions, then rapidly purified by ion exchange chromatography to yield pure products. In some instances, impurities devoid of ionizable functionality can be covalently modified prior to purification. The generic purification sequence is applicable to a variety of reactions, and is amenable to automation with commercially available equipment.

Glutamine-derived aldehydes for the inhibition of human rhinovirus 3C protease

Peptide aldehydes have been synthesized and evaluated as inhibitors of human rhinovirus 3C protease. Those inhibitors containing a C-terminal glutamine aldehyde were prepared using newly developed methodology involving reduction of the corresponding glutarimide, which can be easily prepared from N-protected glutamine. Low molecular weight (<500) compounds with low to submicromolar inhibitory activity in both isolated enzyme and in vitro translation assays have been identified.

Solid phase synthesis of urea libraries using a diversifiable thiophenoxy carbonyl linker

Abstract A method for the solid phase synthesis of urea libraries from primary and secondary amines is described which utilizes a thiophenoxy carbonyl linker. Sequential release of different urea products from a common batch of resin using a “milking” procedure has also been accomplished.

New dipeptide isosteres useful for the inhibition of HIV-1 protease

Abstract A family of readily accessible Phe-Pro mimics has been devised in which ortho-substituted benzamides serve as proline surrogates. When suitably functionalized, these dipeptide isosteres afford potent inhibitors of HIV-1 protease which are also effective in whole cell antiviral assays.

Structure-based drug design of nonpeptidic P2 substituents for HIV-1 protease inhibitors

Abstract The cocrystal structures of LY289612 and LY297135 were used as a starting point in the design of nonpeptidic HIV-1 protease inhibitors. This report details the discovery of a series of novel aromatic P 2 replacement groups. The 3-hydroxy-2-methyl benzoic acid group, discovered in AG1254, was incorporated into the hydroxyethyl amine series to produce the potent antiviral compound (LY309391/ AG1310).

Isophthalic acid derivatives: amino acid surrogates for the inhibition of HIV-1 protease

Using the X-ray crystal structure of the inhibitor 1 complexed to HIV-1 protease, a new series of HIV-1 protease inhibitors was developed incorporating substituted isophthalic acid derivatives as amino acid surrogates. Through iterative structure-based design, the lead compound 2 was optimized to produce a variety of non-peptide HIV-1 protease inhibitors with significant antiviral activity. In contrast to 1, several members of this series exhibit significant oral absorption in animals.

Discovery of (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide, a potent and orally efficacious mGlu5 receptor negative allosteric modulator.

A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain.

Novel bicyclo[3.1.0]hexane analogs as antagonists of metabotropic glutamate 2/3 receptors for the treatment of depression

Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo[3.1.0]hexane glutamic acid analogs as orthosteric (glutamate site) mGlu2/3 receptor antagonists. This work led to the discovery of a highly potent and efficacious tool compound 18 (hmGlu2 IC50 46±14.2nM, hmGlu3 IC50=46.1±36.2nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10mg/kg ip without any significant effects on locomotor activity. Compound 18 thus represents a novel tool molecule for studying the impact of blocking mGlu2/3 receptors both in vitro and in vivo.