David Thomas Parker

Sulfonamide-based hydroxamic acids as potent inhibitors of mouse macrophage metalloelastase

The structural requirements of sulfonamide-based hydroxamic acid 1 for inhibition of macrophage metalloelastase (MME) were investigated. A short aliphatic group at the R2 position together with an aromatic group at the R3 position significantly improved the inhibitory activity. Compounds 32, 34, and 40 were the most potent inhibitors of MME with IC50 values between 5 and 6 nM.

Oral administration of a matrix metalloproteinase inhibitor, CGS 27023A, protects the cartilage proteoglycan matrix in a partial meniscectomy model of osteoarthritis in rabbits.

Matrix metalloproteinases (MMP) are elevated in human osteoarthritic cartilage [1] and in cartilage from rabbits with experimental osteoarthritis (OA) following partial meniscectomy [2]. CGS 27023A is a M M P inhibitor that inhibits stromelysin, collagenase and gelatinase. CGS 27023A is an orally active inhibitor of stromelysin. CGS 27023A at 75 gmoles/kg p.o. inhibits release of proteoglycan into synovial fluid following intra-articular injection of stromelysin into rabbit knees. The purpose of these experiments was to determine whether CGS 27023A would inhibit cartilage proteoglycan loss in a partial meniscectomy model of osteoarthritis in rabbits [3]. Doxycycline was used as a reference drug [4].

Potent Nonimmunosuppressive Cyclophilin Inhibitors With Improved Pharmaceutical Properties and Decreased Transporter Inhibition

Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.

Phosphonic acid analogs of diclofenac: an Arbuzov reaction of trimethylphosphite with an ortho-quinonoid intermediate

Abstract The phosphonic acid analog of the NSAID Diclofenac was efficiently synthesized via an Arbuzov reaction between 2-(2,6-dichloroanilino)benzyl alcohol and trimethyl phosphite followed by TMSBr promoted dealkylation. Seven related phosphonic acids were synthesized using the same novel acid-catalyzed Arbuzov reaction as the key step.

Intra-articular injection of stromelysin into rabbit knees as a model to evaluate matrix metalloprotease inhibitors

Mat r ix me ta l lopro teases ( M M P s ) such as s t romelysin , col lagenase and gela t inase are e levated in the synovial fluids o f pa t ien ts wi th arthri t is . The ext racel lu lar ma t r ix o f car t i lage is suscept ible to deg rada t ion by these proteases . A desi rable p r o p e r t y o f a ma t r ix me ta l lop ro tease inh ib i to r ( M M P I s ) is one tha t inhibi ts ma t r ix me ta l lopro teases f rom degrad ing car t i lage in the joint . W e repor t here our f indings of a mode l tha t tests the d u r a t i o n o f ac t ion and oral b ioava i lab i l i ty o f M M P I s to inhibi t M M P s in the synovia l fluid.

Design, Synthesis, and Properties of a Potent Inhibitor of Pseudomonas aeruginosa Deacetylase LpxC.

Over the past several decades, the frequency of antibacterial resistance in hospitals, including multidrug resistance (MDR) and its association with serious infectious diseases, has increased at alarming rates. Pseudomonas aeruginosa is a leading cause of nosocomial infections, and resistance to virtually all approved antibacterial agents is emerging in this pathogen. To address the need for new agents to treat MDR P. aeruginosa, we focused on inhibiting the first committed step in the biosynthesis of lipid A, the deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by the enzyme LpxC. We approached this through the design, synthesis, and biological evaluation of novel hydroxamic acid LpxC inhibitors, exemplified by 1, where cytotoxicity against mammalian cell lines was reduced, solubility and plasma-protein binding were improved while retaining potent anti-pseudomonal activity in vitro and in vivo.

Novel synthesis of heterocyclic aryl amidines

We have developed a novel amidine synthesis that allows the preparation of heterocyclic amidines that were previously unknown and difficult to prepare by published methods. The route involves the lithiation of heterocycles by the action of n-BuLi followed by reaction with carbon disulfide and trapping with methyl iodide, yielding a dithioate ester. The latter, when heated in 20% methanolic ammonia at 80°C in a sealed tube provides the heterocyclic amidines directly, in good yield. The products are isolated by crystallization of the respective hydrochloride salts.

Chondroprotective Activity of a Matrix Metalloprotease Inhibitor, CGS 27023A, in Animal Models of Osteoarthritis

Breakdown of articular cartilage is a primary feature of osteoarthritis (OA) that leads to loss of joint function. Cartilage degradation involves a progressive loss of proteoglycan matrix and chondrocytes, surface fraying, and erosion. Matrix metalloproteases (MMPs) have been implicated in the destruction of cartilage in OA. CGS 27023A is an orally active inhibitor of stromelysin (MMP-3) and collagenase (MMP-1). CGS 27023A was used to evaluate the effects of an MMP inhibitor on the development of cartilage pathology in a surgical model of OA in rabbits and naturally occurring OA in guinea pigs. Focal OA lesions were produced in rabbits by partial lateral meniscectomy (MNX). Rabbits given CGS 27023A at 100mg/kg in food for 8 weeks following MNX had a lower mean score for cartilage pathology (P <.005) than controls. Spontaneous OA occurs naturally in the knees of guinea pigs, starting during the first 6 months of age and progressing during the next year. By 12 months of age, articular cartilage degeneration including loss of proteoglycan and chondrocytes and surface fibrillation were observed in the medial tibia of the majority of untreated guinea pigs. Guinea pigs administered CGS 27023A in food from 6 months to 12 months of age had reduced histology scores for cartilage lesions (P <.05). These observations support the hypothesis that an MMP inhibitor would ameliorate cartilage destruction by protecting the collagen framework and proteoglycan matrix in OA patients.