Jesse Wong

Discovery of Cyclic Acylguanidines as Highly Potent and Selective beta-Site Amyloid Cleaving Enzyme (BACE) Inhibitors: Part I-Inhibitor Design and Validation

A number of novel amidine containing heterocycles were designed to reproduce the unique interaction pattern, revealed by X-ray crystallography, between the BACE-1 catalytic diad and a weak NMR screening hit (3), with special attention paid to maintaining the appropriate basicity and limiting the number of H-bonding donors of these scaffolds. The iminohydantoin cores (10 and 23) were examined first and found to interact with the catalytic diad in one of two binding modes (A and B), each with the iminohydantoin core flipped 180 degrees in relation to the other. The amidine structural motif within each core forms a bidentate interaction with a different aspartic acid of the catalytic diad. Both modes reproduced a highly conserved interaction pattern between the inhibitors and the catalytic aspartates, as revealed by 3. Potent iminohydantoin BACE-1 inhibitors have been obtained, validating the molecular design as aspartyl protease catalytic site inhibitors. Brain penetrant small molecule BACE inhibitors with high ligand efficiencies have been discovered, enabling multiple strategies for further development of these inhibitors into highly potent, selective and in vivo efficacious BACE inhibitors.

Discovery of Narlaprevir (SCH 900518): A Potent, Second Generation HCV NS3 Serine Protease Inhibitor

Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laboratories, is currently undergoing phase III clinical trials. Detailed investigations toward a second generation protease inhibitor culminated in the discovery of narlaprevir (SCH 900518), 37, with improved potency (∼10-fold over 1), pharmacokinetic profile and physicochemical characteristics, currently in phase II human trials. Exploration of synthetic sequence for preparation of 37 resulted in a route that required no silica gel purification for the entire synthesis.

Discovery of novel nonpeptide tricyclic inhibitors of ras farnesyl protein transferase

A comprehensive structure-activity relationship (SAR) study of novel tricyclic amides has been undertaken. The discovery of compounds that are potent FPT inhibitors in the nanomolar range has been achieved. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit farnesyl protein transferase (FPT) and not geranylgeranyl protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in Cos monkey kidney cells.

Identity of coleonol with forskolin: structure revision of a base-catalysed rearrangement product

Abstract The identity of coleonol and forskolin is shown through structure revision of a rearrangement product isolated earlier from coleonol and is confirmed by direct comparison of authentic coleonol with forskolin 1 ; in addition, coleonol-B should be correctly represented by structure 4 .

Antitumor 8-chlorobenzocycloheptapyridines: a new class of selective, nonpeptidic, nonsulfhydryl inhibitors of ras farnesylation.

Ras farnesylation by farnesyl protein transferase (FPT) is an intracellular event that facilitates the membrane association of the ras protein and is involved in the signal transduction process. FPT inhibition could be a novel, noncytotoxic method of treating ras dependent tumor growth. We report here three structural classes of 8-chlorobenzocycloheptapyridines as novel, nonpeptidic, nonsulfhydryl FPT inhibitors having antitumor activity in mice when dosed orally. We discuss structural and conformational aspects of these compounds in relation to biological activities as well as a comparison to the conformation of a bound tetrapeptide FPT inhibitor.

Discovery and preliminary pharmacology of Sch 37370, a dual antagonist of PAF and histamine

From a series of amide analogs of the histamine H1 antagonist, azatadine, a potent, orally active, dual platelet-activating factor (PAF) and histamine antagonist, Sch 37370, namely 1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-ylidine)piperidine, was discovered. Sch 37370 selectively inhibits PAF-induced aggregation of human plateletsin vitro (IC50=0.6 μM), andin vivo inhibits PAF- and histamine-induced bronchospasm in guinea pigs with ED50 values of 6.0 and 2.4 mg/kg p.o., respectively. Sch 37370 is expected to be more efficacious than single mediator antagonists in allergic diseases, such as asthma.

The discovery of N-((2H-tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822): a potent and selective glucagon receptor antagonist.

A novel series of spiroimidazolone-based antagonists of the human glucagon receptor (hGCGR) has been developed. Our efforts have led to compound 1, N-((2H-tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822), a potent hGCGR antagonist with exceptional selectivity over the human glucagon-like peptide-1 receptor. Oral administration of 1 lowered 24 h nonfasting glucose levels in imprinting control region mice on a high fat diet with diet-induced obesity following single oral doses of 3 and 10 mg/kg. Furthermore, compound 1, when dosed orally, was found to decrease fasting blood glucose at 30 mg/kg in a streptozotocin-treated, diet-induced obesity mouse pharmacodynamic assay and blunt exogenous glucagon-stimulated glucose excursion in prediabetic mice.

Dual antagonists of platelet activating factor and histamine. 2. pyridine ring substitution of N-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidines ☆

Abstract A Series of pyridine ring substituted 1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6] cyclohepta[1,2-b]pyridin-11-ylidene)piperidines which are antagonists of both PAF and histamine were prepared by one of three different methods. Analogs with substituents at C-3 were found to be the best dual antagonists among their corresponding reioisomers. Analogs with an electron donating substituent at the C-3 position are generally better antagonists of both PAF and histamine than analogs with electron withdrawing groups.

Synthesis of 7,8-acetylenic analogs of hexahydro leukotriene-E4 with agonist and antagonist activities: convenient stereoselective routes to E- and Z-enynes

Abstract E- and Z-enynes available by stereoselective dehydrations of Co 2 (CO) 6 completed and uncomplexed propargyl alcohols 13 and 5 produced acetylenic LT-E 4 analogs with contractile activity similar to leukotrienes. Their 5-desoxy analogs were found to have antagonist activity against LT-C 4 induced contractions on isolated guinea pig lung parenchyma.

A Facile and Efficient Synthesis of 3,3-Dimethyl Isopropylidene Proline From (+)-3-Carene

A highly efficient and practical route to 3,4-isopropylidene proline I, starting from (+)-3-carene, was developed. The three continuous stereocenters were constructed using the inherent chirality of the starting natural product 2. The overall yield for the 12-step synthesis is 34%. The optimized sequence leading to 1 has been successfully applied on a multigram scale, thereby establishing the practicality of this route.