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Afid Therapeutics Inc.

The new chemistry

AFID Therapeutics defines and delivers advanced chemical and biochemical technologies and strategies and employs them in the design, discovery, delivery, and development of new drugs. Behind the company is an extensive web of synthetic chemistry patents and expertise covering processes and compositions that allow the preparation of very advanced small molecule drugs and new advanced materials for use in their delivery.

New introductions as of July 2008

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See our "Products" page for a complete listing. Compounds are available in quantities of 100 mg, 200 mg, 500 mg, 1 gram and 5 grams. Many compounds are now available in 10 gram to over 100 gram quantities and we can produced some in Kg quantities to support customer development programs and trials. send an e-mail to sales@afidtherapeutics.com or call for pricing

Recent introductions to the product line

Amino acids Download SD file

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Chiral diamines Download SD file

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Established Products

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hydroxy-cyclopentane-acids-derivs

hydroxy-cyclopently-acetic-acids

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These are examples of the various compound classes we have available for our customer base. Go to our products section to see a full listing. We can prepare specially modified, protected or activated version of these at your request. We can also prepare specialized subcollections at special pricing. Compounds are available in quantities of 100 mg, 200 mg, 500 mg, 1 gram and 5 grams. Many compounds are now available in 10 gram to over 100 gram quantities and we have produced some in over 1 Kg quantities to support customer development programs.

Special compound collections

The new chemistry...chirality, functionality, flexibility, tunability, accessibility, novelty. Compounds in the ADLIB collection are all new compositions of matter and have never been made or screened before. The structures are based on a consideration of the structural attributes of known and calculated pharmacophores. New ADLIB libraries are being introduced periodically with new themes aimed at targets including: Nucleases, kinases, phosphatases, glycosidases, glycosyl transferases, monamine oxidases, topoisomerases, DNA, RNA, aldolases, proteases, ribosomes and other important therapeutic foci.

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The Company has a library of over 3000 novel oxazolidinone structures some of which show antimicrobial activity comparable to the industry standard Zyvox^TM. Access to these was facilitated by the development of a comprehensive synthetic strategy that allows selective placement of chemical functionality around the oxazolidinone nucleus (see below).

Click on our "products" or "services" pages for more

Tomorrow's chemistry today

discovery

We specializes in chiral small ring and acyclic compounds with multiple chiral centers. Small ring systems such as tetrahydrofurans, pyrrolidines and cyclopentane derivatives are a special focus. Over 80% of our compounds are new. New chiral amines and acids are a specialty.

The AFID Therapeutics technology base utilizes the structural richness of carbohydrates and to will allow intervention and therapies across a wide span of the disease spectrum. Diseases include bacterial and viral infections, cancer, autoimmune disorders, cardiovascular disorders, diabetes, and Alzheimer's and other neurological disorders. Drug targets include kinases, phosphatases, nucleases, glycosidases, glycosyltransferases, ribosomes, cell membranes and nucleic acids.

Chiral 5-membered ring systems and the central roles they play in drug design: Nucleic acid building blocks and metabolites are rich in chirality largely because of the ribose and deoxy ribose 5-membered carbohydrate rings. Small ring systems that can act as surrogates and analogs for the ribose and deoxyribose moieties of nucleosides and nucleotides are in great demand for drug development. Credible chemical functionality and chirality are very important in the design of these analogs.

In general, the preparation of small ring systems that resemble sugar rings, nucleosides and nucleoside derivatives even on a small is very challenging. The practice of such chemistry on a commercial scale to aid drug discovery and development and eventually support drug synthesis is even more challenging. There is a clear unmet need for advanced chemistries in this area.

Analogs of nicotine and muscarine are important candidates for drugs that function by interacting with acetylcholine (cholinergic) receptors. Cholinergic receptors are coupled to G proteins, a family of intramembrane transducers that regulate signal transduction through second messenger systems. Pathological changes in neurotransmission mediated by cholinergic receptors are thought to be responsible for the early clinical manifestations of Alzheimers. These manifestations include loss of short term memory, judgment, cognition and orientation. Muscarinic receptors have become important therapeutic targets for the design of small molecules agonists that might improve cognitive function in patients with Alzheimers. Muscarinic agonists also affect biological functions such as sweating, the secretion of digestive glands, heart rate, constriction of the pupils and the function of muscles that control respiration, digestion and urination. This has opened up entire arenas for therapeutic intervention. Nicotine is also known to enhance some cognitive functions. These include learning and memory. This is thought to occur through activation of brain nicotinic acetylcholine receptors. The list of potential therapeutic uses for drugs that exert their action through nicotinic acetylcholine receptors is rather impressive and included the treatment of Alzheimers and Parkinsons diseases, the treatment of pain, schizophrenia, depression, attention deficit disorder, Tourette’s syndrome, epilepsy, depression, anxiety and drug abuse. The structures of muscarine and nicotine are shown below. Note the similarity of the structure of muscarine to deoxyribose and the chiral 5-membered ring in nicotine.

nicotine-muscarine

Chiral cyclopentanols as core structures for drug development: One area that we have been actively commercializing is the development of new synthetic routes to chiral cyclopentane derivatives. Functionality in the cyclopentane ring includes hydroxy groups, carboxylic acid and amino groups. These are further modified in our product offerings to expand the synthetic scope and design utility for our customers. This product line is aimed at providing the pharmacologically active structures that can approximate the nucleoside sugars or the ring in muscarine. These are two of the major challenges facing drug development. The availability of these chiral, flexible small-ring systems is aiding drug discovery and development efforts in companies with therapeutic strengths in antivirals, cancer and neurological disorders.

The chiral cyclopentanols shown to the left are largely not available anywhere else. The amino and carboxylic acid functionalities allow easy modification and integration into synthetic schemes for drug discovery activities. They can also serve as key functionalities in drug design.

Chiral pyrrolidines as core structures for drug development: Pyrrolidines play critical roles in the design of drugs. The 5-membered ring in nicotine is a chiral pyrrolidine system and the availability of chemistries for this is obviously important for the design of nicotinic receptor agonists and antagonists. The pyrrolidine ring is also a crucial molecular analog of the transition state formed in the replacement of the anomeric group in nucleosides. One case in point is the transformation of inosine to ribose-1-phosphate catalysed by the enzyme purine nucleoside phosphorylase (PNP)

pnp

PNP inhibitors are only a small part of the story about the utility of “aza” (nitrogen instead of oxygen in the ring) versions of ribose and deoxy ribose. They are generally excellent glycosidase inhibitors and have been explored in a variety of pharmaceutical contexts especially in the areas of cancer and antivirals (39). Access is very challenging.

Imino-sugars (also called azasugars) are important glycosidase and glycosyl transferase inhibitors with very high potential as drugs. Their potential therapeutic applications range from the treatment of diabetes to cancer and AIDS. Iminosugars are excellent drug candidates for diabetes therapy. An even more exciting potential use is in the treatment of cancer and viral diseases. Their synthesis is difficult and challenging.

Central to the AFID Therapeutics strategy for developing new therapeutics based on carbohydrate, nucleic acid and nucleoside processing is the generality of the mechanisms involved. Glycosidases, glycosyltransferases and N-glycanases are enzymes that are responsible for carrying out a wide spectrum of cellular processes and together represent one of the largest superfamilies of enzymes known. Several extremely debilitating and eventually fatal diseases such as diabetes, arthritis and several organ disorders are caused or mediated by carbohydrate processing. Abnormal cell surface glycosylation characterizes several cancers. Many infectious diseases are also mediated by glycosylation.

The chemistry of the glycosidic linkages in nucleosides and nucleotides deserves special attention as targets for developing therapeutics. The manganese dependent nucleoside processing enzyme called Hypoxanthine-guanine phosphoribosyltransferase (HGPRT), if absent in humans, results in Lesch-Nyhan syndrome. Hyperuricemia and neurological disorders are features of this disease. This enzyme is also targeted as a drug strategy in the treatment of protozoan parasites such as Plasmodium the causative agent of malaria. Purine nucleoside phosphorylase is another nucleoside processing enzyme that is targeted for the treatment of a variety of diseases including cancer and autoimmune disorders. Nucleoside hydrolases are also potential targets. These are involved in the salvage and regulation of purine and pyrimidine pools. They also are involved in base excision repair and in the inactivation of ribosomes.

Means of inhibiting or regulating glycosidases and glycosyl transferases, especially by small organic molecules, are much sought after in drug development. Very few inhibitors are obtainable in sufficient quantity to support drug development. Most are obtained as natural product isolates and then only in very limited quantities. There are very few synthetic candidates and most are not viable for a variety of reasons. These include poor specificity, toxicity and intractable synthetic routes because of the high density of functional groups and asymmetric centers in these molecules. AFID Therapeutics has design strategies, synthetic methods, key intermediates and library collections for new compound classes that are capable of modulating and directing the chemical processes involved in the formation and breakage of glycosidic linkages in biological systems.

Changes in carbohydrate chemistry at the cell surface or in metabolic pathways are key features (both cause and association) of a wide spectrum of diseases, as follows:

Cancer

o Leukemia

o Hodgkin’s disease

o Melonomas

o Sarcomas

o Advanced ovarian cancer

o Oropharyngeal tumors

o Breast cancer

o Prostate cancer

· Diseases of Major Organs

o Liver diseases

o Diabetes-induced cardiac hypertrophy

· Auto-immune Disorders

o Arthritis

Analogs of the critical transition state structures at the center of the formation or modification of these carbohydrate species are being seriously evaluated as therapeutic strategies for these diseases. AFID Therapeutics has an extensive intellectual property holding in this area. This includes both composition of matter and process patents. These will be licensed out for use in applications not pursued by AFID.

Chemical technology that allows the rapid synthesis of compound libraries is an important asset in drug discovery. This allows the comprehensive evaluation of structure / function space. Detailed models can then be developed and more accurate predictions on which structures have which activities can be made. AFID Therapeutics has access to such technologies in all aspects of its drug discovery and delivery program. Chemistries for the preparation of chiral amides, esters, lactones, pyrrolidinones, epoxides, oxazolidinones, pyrrolidines, iminopentitols, iminohexitols and other classes of compounds are available.

SPECIAL COMPOUND COLLECTIONS

1 mg of each compound in 500 microliters DMSO.

Library ADLIB-00001 (blue library)

00001A and 00001C: These compounds are aza-analogs of ribose. The compound class is an iminopentitol. These molecules are very challenging to make and they are used to inhibit the formation or breakage of bonds in RNA synthesis or repair. They function as transition state inhibitors. They also inhibit the enzyme PNP (purine nucleoside phosphorylase) which is an important enzyme in the purine salvaging pathway and is an important target for some cancers. This family of molecules is not available commercially elsewhere. If there is increased turnover of DNA or RNA after radiation damage then the levels of these enzymes should be very much elevated making such compounds good candidates as adjunct therapies. Other compounds in this class are 00003A, 00003C and 00003F in collection ADLIB-00003 (the green library). “Di-deoxy” analogs of these compounds include 00001B, 00001C, 00001E, 00001F, 00001G, 00001H, 00001I and 00001J. The differences in charge and hydrophobicity should mediate binding affinity. It should be noted that aza-compounds are readily converted to reactive species by radiation especially through the formation of N-oxides. They also readily penetrate cell membranes including the nuclear membranes because of the positive charge among other functionality. Many of them can potentially act as chain terminators.

Library ADLIB-00002 (black library)

The compounds are mainly targeted at adrenergic receptors. They are analogs of epinephrine. Compounds 00002F and 00002G have a 2’-deoxy aza-ribose substructure and should impact nucleic acid processing.

Library ADLIB-00003 (green library)

As noted earlier several compounds here should inhibit nucleic acid synthesis and processing. Many of the other molecules in this class are aimed at kinase inhibition. This is especially true of 00003C, 00003G, 00003E that feature quinoline and isoquinoline groups especially in sulfonamide linkages. The sulfates and phosphates are analogs of nucleotides are aimed at antiviral and cancer applications. Other nucleoside analogs include 00003B, and 00003H which can impact nucleic acid synthesis and processing by inhibiting a variety of enzymes including kinases, nucleases and phosphatases.

Library ADLIB-00004 (gold library)

This collection is aimed at glycosyl transferases and glycosidases and are especially targeted at inhibiting or regulating general carbohydrate metabolism and protein glycosylation. Known compounds in this structure class include swainsonine and deoxynojirimycin. Quine and isosuinoline sulfonamide functionality is included in some as a “wild card” to give kinase inhibitory functionality.

Library ADLIB-00005 (purple library)

This library features two exciting compounds ADLIB-00005A and ADLIB-00005C which should be good substrates for TK (thymidine kinase) allowing them to be incorporated into DNA. Once there the radiation chemistry should be remarkable because of the potential for forming excited species that should cause eliminations, adduct formation and insertions. Other compounds in this collection include potential kinase inhibitors , protease inhibitors and glycosyl transferase and glycosidase inhibitors.

Our screening collections feature piperazines, piperidines, oxazolines, oxazolidinones, morpholines, pyrrolidines, pyrrolidones, aza-sugars, macrolides, lactones, lactams, thiolactams, cyclopentanes, furans, pyrans, quinolines, isoquinolines, quinolones, purines, pyridines, pyrimidines, imidazoles, benzimidazoles, triazoles, sufonamides, phosphates, phosphonates, sulfates, sulfonates, alcohols, acids, amines, epoxides and several other compound classes.