Discovery and Structure−Activity Relationship of Oxalylarylaminobenzoic Acids as Inhibitors of Protein Tyrosine Phosphatase 1B

Abstract

Protein Tyrosine phosphatase 1B (PTP1B) has been implicated as a key negative regulator of both insulin and leptin signaling pathways. Using an NMR-based screening approach with 15N- and 13C-labeled PTP1B, we have identified 2,3-dimethylphenyloxalylaminobenzoic acid (1) as a general, reversible, and competitive PTPase inhibitor. Structure-based approach guided by X-ray crystallography facilitated the development of 1 into a novel series of potent and selective PTP1B inhibitors occupying both the catalytic site and a portion of the noncatalytic, second phosphotyrosine binding site. Interestingly, oral biovailability has been observed in rats for some compounds. Furthermore, we demonstrated in vivo plasma glucose lowering effects with compound 12d in ob/ob mice.

Chromium picolinate and biotin combination improves glucose metabolism in treated, uncontrolled overweight to obese patients with type 2 diabetes

“…PTP-1B has long been implicated in the regulation of insulin receptor tyrosine phosphorylation and tyrosine kinase activity [50], and has been validated as a bona fide pharmacological target for increasing insulin sensitivity [51][52][53][54][55]. In animals, small molecules that inhibit PTP-1B increase insulin sensitivity and lower plasma glucose [56][57][58]. Alternatively, chromium might act directly on the insulin receptor, and increase its tyrosine kinase activity [59], as has been observed with other small molecules [60,61].…”

Protein Tyrosine Phosphatase 1B Inhibitors: A Molecular Level Legitimate Approach for the Management of Diabetes Mellitus

“…As the basic structures of these inhibitors are charged, reasonable bioavailability was reported in rats. 143 From the SAR studies of the above reported series, various structural modifications have been attempted for higher and selective PTP 1B inhibitory activity. Various flexible linkers such as aminopentanoic acid (81) and phenylethylaminopentanoic acid (82) (Table XV) along with chiral amino sulfide such as (83) and (84) (Table XVI) showed increasing inhibitory potency as well as moderate selectivity.…”

Toward the discovery of small molecule PTP1B inhibitors for the treatment of metabolic diseases

“…2, CMS) and related acids Liljebris et al, 2002] and oxalylaminobenzoic (Fig. 2, OBA) and related acids Liu et al, 2003a] have been used as pTyr mimetics but still yield molecules that carry a strong negative charge at physiological pH. While attempts have been made to replace the carboxylic acids with bioisosteres, such as tetrazole with reduced anionic charge and improved permeability , they have not led to molecules with sufficient overall properties to be considered as drug candidates.…”