Jenny Tan

Non-peptidic inhibitors of neutral endopeptidase 24.11 1. Discovery and optimization of potency

Abstract Although based on a single α-amino acid residue, N -phosphonomethyl-(S)-(4-phenyl)phenylalanine ( 2 ) was discovered to produce strong inhibition of the zinc metalloprotease, neutral endopeptidase (NEP 24.11). Structural optimization of this new lead culminated with the design of the phosphonic acid tetrazole 17 (CGS 26303), a non-peptidic and extremely potent NEP inhibitor.

Potent non-peptidic dual inhibitors of endothelin-converting enzyme and neutral endopeptidase 24.11 ☆

Abstract Structural modifications of CGS 26303, a non-peptidic α-aminophosphonate dual ECE/NEP inhibitor lead, were performed to maximize inhibition of recombinant human ECE-1, while maintaining strong NEP inhibition. Specifically, substitution of the α-aminophosphonate moiety with aryl ethyl side-chains led to the discovery of a new class of potent, non-peptidic, dual inhibitors, such as CGS 31447, which blocked ECE-1 and NEP activities with IC50s of 17 and 5 nM, respectively.

Discovery of Orally Active Carboxylic Acid Derivatives of 2-Phenyl-5-trifluoromethyloxazole-4-carboxamide as Potent Diacylglycerol Acyltransferase-1 Inhibitors for the Potential Treatment of Obesity and Diabetes

Diacylglycerol acyltransferase-1 (DGAT-1) is the enzyme that catalyzes the final and committed step of triglyceride formation, namely, the acylation of diacylglycerol with acyl coenzyme A. DGAT-1 deficient mice demonstrate resistance to weight gain on high fat diet, improved insulin sensitivity, and reduced liver triglyceride content. Inhibition of DGAT-1 thus represents a potential novel approach for the treatment of obesity, dyslipidemia, and metabolic syndrome. In this communication, we report the identification of the lead structure 6 and our lead optimization efforts culminating in the discovery of potent, selective, and orally efficacious carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-carboxamides. In particular, compound 29 (DGAT-1 enzyme assay, IC(50) = 57 nM; CHO-K1 cell triglyceride formation assay, EC(50) = 0.5 μM) demonstrated dose dependent inhibition of weight gain in diet induced obese (DIO) rats (0.3, 1, and 3 mg/kg, p.o., qd) during a 21-day efficacy study. Furthermore, compound 29 demonstrated improved glucose tolerance determined by an oral glucose tolerance test (OGTT).

Synthesis and biological activity of phenoxyphenyl oxamic acid derivatives related to L-thyronine.

The synthesis of substituted phenoxyphenyl oxamic acid derivatives related to L-thyronine (L-T3) is described. The in vitro and in vivo cholesterol lowering and cardiovascular effects of these compounds are presented and discussed.

Dual inhibition of neutral endopeptidase and angiotensin-converting enzyme by N-phosphonomethyl and N-carboxyalkyl dipeptides

Abstract Structural modifications have been performed on the selective α-amino phosphonic acid NEP inhibitor CGS 24592, to achieve dual ACE/NEP inhibition in vitro. (S)-N-Phosphonomethyl-valyl-(S)-(4-phenyl)phenylalanine (19) is representative of a new type of phosphorus-containing ACE/NEP inhibitors, approaching the in vitro potency of the sulfhydryl ACE inhibitor captopril and the NEP inhibitor thiorphan.

Synthesis and biological activity of potent heterocyclic thiol-based inhibitors of endothelin-converting enzyme-1

Directed screening of metalloprotease inhibitors identified CGS 30084 (1) as a potent inhibitor of endothelin-converting enzyme-1 (ECE-1) in vitro (IC(50)=77 nM). Herein we report the syntheses and biological activities of analogues containing modified biphenyl moieties, bearing heterocyclic proximal rings. Compound 20, the thioacetate ethyl ester prodrug derivative of compound 19a, was found to be an orally active and potent inhibitor of ECE-1 activity in rats.

Synthesis of tetrazole analogs of α-amino acids by alkylation of a Schiff base of α-aminomethyltetrazole

Abstract A benzophenone imine of N-1 protected α-aminomethyltetrazoles was found to undergo alkylation with organic halides in good yields. Deprotection afforded tetrazole analogs of α-amino acids.