Philip E.J. Sanderson

A one-pot conversion of the phenyldimethylsilyl group into a hydroxyl group

Abstract A phenyldimethylsilyl group attached to carbon can be converted into a hydroxyl group using either bromine or mercuric ion in an acetic acid solution of peracetic acid.

Small, noncovalent serine protease inhibitors.

Thrombin and factor Xa (fXa) are the only serine proteases for which small, potent, selective, noncovalent inhibitors have been developed, which are ultimately intended as drug development candidates (in this case as anticoagulants). Noncovalent inhibitors may be more selective and chemically and metabolically less reactive than covalent inhibitors. In addition, noncovalent inhibitors are more likely to have fast‐binding kinetics which is particularly important in the development of thrombin inhibitors. TAME derived noncovalent thrombin inhibitors argatroban, napsagatran, and UK 156,406 have entered clinical trials as anticoagulants, the latter as an orally active agent. Serine trap deletion from substrate‐like peptides led to the development of inogatran and melagatran, both of which have entered clinical trials as intravenous agents. The use of 3‐aminopyridinone and pyrazinone acetamide peptidomimetic templates has resulted in the development of L‐375,378 which has been chosen for clinical development as an orally active anticoagulant. Recently, compounds which do not have the conventional hydrogen bonding capabilities of peptides have begun to appear in the thrombin literature. Publications on noncovalent fXa inhibitors cover this type of peptidomimetic almost exclusively.

L-374,087, an efficacious, orally bioavailable, pyridinone acetamide thrombin inhibitor

Replacement of the amidinopiperidine P1 group of 3-benzylsulfonylamino-6-methyl-2-pyridinone acetamide thrombin inhibitor L-373,890 (2) with a mildly basic 5-linked 2-amino-6-methylpyridine results in an equipotent compound L-374,087 (5, Ki = 0.5 nM). Compound 5 is highly selective for thrombin over trypsin, is efficacious in the rat ferric chloride model of arterial thrombosis and is orally bioavailable in dogs and cynomolgus monkeys. The structural basis for the critical importance of both methyl groups in 5 was confirmed by X-ray crystallography.

Potent, orally bioavailable somatostatin agonists: Good absorption achieved by urea backbone cyclization

Backbone cyclization of urea-based somatostatin agonists resulted in novel, orally bioavailable agonists. Binding assays confirmed that the resulting conformationally constrained cyclic ureas retained the potency of their acyclic counterparts. SAR studies subsequently led to highly potent analogs, selective for receptor subtype 2, and having good oral bioavailability.

Chapter 8. Anticoagulants: Inhibitors of thrombin and factor Xa

Publisher Summary This chapter elaborates the inhibitors of thrombin and factor Xa (fXa) that are members of the trypsin family of serine proteases and pivotal components of the blood coagulation cascade. Thrombin is the final enzyme of the cascade. Its primary actions are to cleave fibrinogen to release fibrin and to activate platelets via the thrombin receptor and, since polymerized fibrin and activated platelets are the principal components of blood clots, thrombin inhibition ameliorate coagulation. The X-ray crystal structure of benzothiazole carboxylic acid derivative RWJ-51438 bound to thrombin was reported. It shows the heterocycle occupying the S1′ site with an edge to face contact with the indole of Trp-60D similar to the bound structure of parent compound RWJ-50353. Melagatran and its oral pro-drug H 376/95 are well advanced in clinical trials and preliminary results from the METHRO II dose-response study comparing them with the low molecular weight heparin (LMWH) daltaparin as thromboembolic prophylaxis after total hip or total knee replacement were reported.

L-373,890, an achiral, noncovalent, subnanomolar thrombin inhibitor

Abstract L-373,890, a highly selective and efficacious pyridinone acetamide thrombin inhibitor was designed using a combination of X-ray crystallography, molecular modeling and empirical structure optimization.

Azaindoles: Moderately basic P1 groups for enhancing the selectivity of thrombin inhibitors

Starting from a 2-amino-6-methylpyridine P1 group and following a strategy of enlarging it whilst reducing its polarity, we have developed a series of potent, moderately basic azaindoles which are intrinsically much more selective for thrombin versus trypsin. Certain pyrazinone acetamide azaindole derivatives have pharmacokinetic parameters after oral administration to dogs, or efficacy in vitro, comparable to an optimized pyrazinone acetamide 2-amino-6-methylpyridine derivative.

C6 modification of the pyridinone core of thrombin inhibitor L-374,087 as a means of enhancing its oral absorption.

1 (L-374,087) is a potent, selective, efficacious, and orally bioavailable thrombin inhibitor that contains a core 3-amino-2-pyridinone moiety. Replacement of the C6 pyridinone methyl group of 1 by a propyl group gave 5 (L-375,052), which retained all the excellent properties of 1, and also yielded higher plasma levels after oral dosing in dogs and rats.

The phenyldimethylsilyl group as a masked hydroxy group

A phenyldimethylsilyl group attached to carbon can be converted into a hydroxy group 1→5, with retention of configuration at the migrating carbon, by any of three main methods. The first involves protodesilylation, to remove the phenyl ring from the silicon atom, followed by oxidation of the resulting functionalised silicon atom using peracid or hydrogen peroxide. The second uses mercuric acetate for the same purpose, and can be combined in one pot with the oxidative step using peracetic acid. This method has a variant in which the mercuric ion is combined with palladium(II) acetate, both in less than stoichiometric amounts. The third uses bromine, which can also be used in one pot in conjunction with peracetic acid. In this method, but not in the method based on mercuric acetate, the peracetic acid may be buffered with sodium acetate. The method using bromine as the electrophile for removing the benzene ring has a more agreeable variant in which it is administered in the form of potassium bromide, which is oxidised to bromine by the peracetic acid. The scope and limitations of each of these methods are reported with a range of examples possessing between them many of the common functional groups. Simple benzene rings, alcohols, ethers, esters, amides and nitriles are compatible with all three methods, and ketones do not undergo Baeyer–Villiger reaction under any of the conditions. Amines, however, are oxidised to amine oxides. Ketones may be brominated in the third of the three main recipes. The absence of acid in the third method makes it especially valuable when the phenyldimethylsilyl group has a neighbouring nucleofugal group such as hydroxy or acetoxy. Carbon–carbon double bonds are incompatible with the methods, except for terminal monosubstituted double bonds, which can survive the conditions used in the first of the three methods.

The synthesis of thrombin inhibitor L-370,518 via an α-hydroxy-β-lactam

Abstract We describe an efficient synthesis of thrombin inhibitor L-370,518 ( 1 ) via β-lactam 2 . The synthesis of 2 is carried out in six steps from 4-aminocyclohexane carboxylic acid, with a yield of 27%.