Martha L. Minich

Discovery of (S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid as a Hepatoselective Glucokinase Activator Clinical Candidate for Treating Type 2 Diabetes Mellitus

Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic β-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.

Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2.

Screening Pfizers compound library resulted in the identification of weak acetyl-CoA carboxylase inhibitors, from which were obtained rACC1 CT-domain co-crystal structures. Utilizing HTS hits and structure-based drug discovery, a more rigid inhibitor was designed and led to the discovery of sub-micromolar, spirochromanone non-specific ACC inhibitors. Low nanomolar, non-specific ACC-isozyme inhibitors that exhibited good rat pharmacokinetics were obtained from this chemotype.

Pyridones as glucokinase activators: Identification of a unique metabolic liability of the 4-sulfonyl-2-pyridone heterocycle

A promising area of novel anti-diabetic therapy involves identification of small molecule activators of the glucokinase enzyme to reduce blood glucose and normalize glucose stimulated insulin secretion. Herein, we report the identification and optimization of a series of 4-sulfonyl-2-pyridone activators. The activators were evaluated for in vitro biochemical activation and pharmacokinetic properties. As part of these efforts, a unique metabolic liability of the 4-sulfonyl-2-pyridone ring system was identified wherein this heterocycle readily undergoes conjugation with glutathione under non-enzymatic conditions.

Application of hygromycin a structure activity relationships to the antibiotic A201A.

Abstract Replacement of the disaccharide portion of A201A with an allyl ether, with concomitant 3-hydroxylation, affords an analog with biological activity comparable to that of the natural product. The response of biological activity to this modification closely parallels that observed with hygromycin A, which implies that these two natural products may share a common binding site.

Synthesis and vitro antibacterial activity of hygromycin a analogs modified at the C4′ aryl position

Abstract A variety of hygromycin A analogs are described which contain modifications of or replacements for the natural sugar. Antibacterial activities against Serpulina (Treponema) hyodysenteriae , an important animal health pathogen, are reported and indicate that small lipophilic C 4′ substituents serve as useful sugar surrogates in the hygromycin A class.

Semisynthetic modification of hygromycin A. 1. Synthesis and antibacterial activity of vinyl methyl and amide analogs.

Abstract Formation of the peracetate of hygromycin A, followed by sodium borohydride reduction and oxidative cleavage, affords an aldehyde which serves as a key intermediate for preparation of vinyl methyl and amide analogs. Several analogs of each type were prepared and tested for activity against Serpulina hyodysenteriae, the causative organism of swine dysentery.

Cyclic homopentapeptides. 1. Analogs of tuberactinomycins and capreomycin with activity against vancomycin-resistant enterococci and Pasteurella

Abstract A 6a-(3′,4′-dichlorophenylamino) analog of viomycin was uncovered by a high-throughput screen against the animal health pathogen Pasteurella haemolytica, and has served as a novel lead structure for our infectious disease programs. We report herein the synthesis and activity of analogs of tuberactinomycins and capreomycin that are active against Pasteurella spp., methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci. This paper describes the synthesis and activity of some C-6a-substituted analogs of tuberactinomycins and capreomycin, which are active against Pasteurella spp., methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci.

Semisynthetic modification of hygromycin A. 2. synthesis and antibacterial activity of aryl analogs.

Abstract Syntheses of analogs exploring the SAR of the aryl region of hygromycin A are described. Antibacterial activities against Serpulina (Treponema) hyodysenteriae and Pasteurella multocida, two key animal health pathogens, are reported.

Synthesis and in vitro antibacterial activities of novel conformationally restricted hygromycin A analogues

Abstract The preparation of semisynthetic conformationally restricted hygromycin A analogues are described. Antibacterial results from these compounds suggest active conformations for this class of agents.

Semisynthetic modification of hygromycin A. 3. synthesis and antibacterial activity of aminocyclitol analogs.

Abstract A series of aminocyclitol-modified analogs of hygromycin A has been prepared, including three derivatives exploring the effect on biological activity of methylation of each of the three hydroxyl groups. Antibacterial activities against Serpulina hyodysenteriae and Pasteurella multocida , two important animal health pathogens, are presented.