Therapeutic profile: Diabetic complications Although it has recently been demon- strated in a large diabetic control and complications clinical trial [The DCCT Research Group, New Eng1.J. Med. (1993) 329, 977-9861 that intensive insulin treat- ment successfully delays the onset and retards the progression of diabetic nephropathy, neuropathy and retinopa- thy, the resulting increased risk of severe hypoglycemia demands the investigation of new therapeutic approaches. The inh- bition of aldose reductase, an enzyme activated during hyperglycemia, and responsible for the conversion of glucose to sorbitol by the polyol pathway, has been a popular approach, leading to a number of recent clinical candidates. Tolrestat 1 and epalrestat 2 have been the most successful of these.

CH,O

s

a%H2co*H 0

2

For diabetic nephropathy, antihyper- tensive treatment is beneficial. Interven- tion in the renin-angiotensin cascade has been a particular target, with angio- tensin II antagonists, such as valsartan 3 [Ciba Geigy AG, WO 95/249011, renin inhibitors [Abbott Laboratories, WO 92/223131 and ACE inhibitors such as captopril [Med. Lett. Drugs 7ber. (1994) 36, 46-471 being used. The combination of ACE inhibitors with calcium channel antagonists has also been examined clinically [Bakris, G.L. and Williams, B. J. Hypertens. (1995) 13, S95-SlOll. Monotherapy with calcium channel antagonists, such as nitrendipine 4, may also have use [Bretzel, R.G. et al. Am. J Kidney Dis. (1993) 21, 53-641.

Prostaglandin E, has also been of use in cases of diabetic nephropathy, presumably through its action on

HN, .N

3 td

/Y-NN02

4

the renin-aldosterone system [Okada, S. et al. J. ht. Med. Res. (1993) 21, 1261321. The potential benefit to patients of the modulation of prosta- noids by the thromboxane synthetase inhibitor ozagrel in diabetic nephro- pathy [Umeda, E et al. J. Diabetes Complications (1995) 9! 334-3361 and by the dual thromboxane A, receptor antagonistithromboxane A, synthetase inhibitor KDI-792 in diabetic neuro- pathy [Ono! Y. et al. Prostaglandins Leukottienes Essent. Fatty Acids (1995) 53, 139-1451 has also been recently described. Other agents that have been investigated clinically include y-lino- lenic acid, gangliosides (nerve tissue sialoglycolipids that may stimulate nerve regeneration), mexiletine, tri- cyclic antidepressants (acting on noci- ceptive pathways), capsaicin (a sub- stance P modulator), a-lipoic acid (an anti-oxidant preventing nerve dysfunc- tion), pentoxifylline (acting on micro- circulatory abnormalities) and amino- guanidine (an inhibitor of advanced glycosylation end-product formation). Advanced glycosylation end-product formation has been implicated, in par- ticular, in the renal dysfunction associ- ated with late stage diabetes. Other compounds acting on this axis include pimagedine (in Phase II) and the back- up compound ALT-946.

Glycation inhibitors such as asco- chlorin can be used to treat diabetic neurosis [Immuno Japan KK, . WO 94/052741. Treatment with modulators of growth hormone can be appropriate, for example treatment of proliferative diabetic retinopathy with the somato-

statin analogue SMS 201-995 (which slows down growth hormone secre- tion) has benefit in patients. Inhibition of growth hormone releasing hormone (GH-RH) is a related area of research with novel peptide analogues of human GH-RH(l-29)NH, reportedly having anatagonist properties [Tulane Edu- cational Fund, WO 95/167071. Diabetic nephropathy could theoretically also be treated by administering a complex of insulin-like growth factor (a mediator of the effects of growth hormone) and insulin-like growth factor-binding pro- tein [Celtrix Pharm Inc., WO 95/138241. Sulodexide is a glycosaminoglycan extracted from mammalian intestinal mucosa and is active in the clinical treat- ment of diabetic nephropathy [Alfa Wassermann SPA, EP 6243741. Related glycosaminoglycans have beneficial effects in animal models [Alfa Wasser- mann SpA, EP 5135131 with one plau- sible explanation being the normaliz- ation of substance P and Met-enkephalin levels. Acetyl-L-carnitine may be active for similar reasons in diabetic neuropa- thy [Drugs Fut. (1995) 20, 991-9951. The involvement of endothelin in diabetic nephropathy has been suggested, so another logical approach is the use of peptide endothelin antagonists [Fujisawa Pharmaceutical Co. Ltd, WO 93/10144; Takeda Chem. Ind. Ltd, EP 6474491. Modulation of endothelial cell activity is a topic of great recent inter- est. A series of naphtho[l,2-blpyrans, typified by 5, inhibit endothelial cell activation in vitro, and this activity trans- lates into in vivo models of glucose and diabetes-induced vascular dys- function [Eli Lilly and Co., US 52816191. Inhibitors of angiogenesis, such as 6,

N4

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H2 . / & v /N

y&y 6 a

DDT Vol. 1, No. 5 May 1996 Copyright 0 Elsevier Science Ltd. All rights reserved. 1359.6446/96/$15.00 221

acting through inhibition of basic fibroblast growth factor-stimulated endothelial cell proliferation, may be active in diabetic retinopathy [US Dept Health and Human Services, WO 95/083271.

With so many approaches being actively investigated across the world, new therapies for the long-term complications of diabetes are clearly within reach of pharmaceutical companies.

Colin P. Dell Lilly Research Centre, Eli Lilly & Co Ltd

Windlesham, Surrey; UK

Combinatorial chemistry Synthesis of dihydropyridines Combinatorial chemists have rapidly increased the range of chemistry on solid- phase to include a number of classical pharmacophoric series. One such class of compound is the dihydropyridines (DHPs), a structure synonymous with calcium channel blocking activity. Re- cently workers from Affymax have described a successful synthesis of DHPs on solid-phase [Gordeev, M. F. et al. J. Org. Chem. (1996) 61,924-9281. Using an amino-derivatized resin, formation of an amino crotonate 1 was followed by con- densation with a ketoester and an alde- hyde to produce the DHP 2. The route

1

0 Ar 0

RO R

TFA

0 Ar 0

RO I7

222

was exemplified by the synthesis of a number of DHPs including the well- known agents nifedipine, nitrendipine and nimodipine.

Linkers for increased diversity Linkers are a particularly effective way of enhancing combinatorial library diversity, as the ability to reveal a new functionality following cleavage from the solid phase may readily generate new classes of struc- ture. A novel use of the ubiquitous Rink resin has been described that yields sulphonamides following acid-catalysed cleavage [Spear, K.L. et al. Tetrahedron Lett. (1996) 37, 1145-11481. The authors demonstrated that the sulphonamide functionality was compatible with N-alkyl- ation and the use of Heck and Stille cou- plings, and this is likely to be a valuable extension of the utility of this solid phase.

(i) KOtBu, BnBr (ii) TFA

>

Me

Reaction optimization Combinatorial chemistry is being widely used to generate new compounds for

screening and drug discovery. However, it is only now beginning to be used as a method for reaction optimization, and thus for process development. Burgess and coworkers’ reactions [Angew. Gem. ht. Ed. En@. (1996) 35, 220-2221 have described the use of a combinatorial approach to the discovery of new metal- based catalysts for carbene C-H insertion. Some 96 different reaction conditions were examined in microtitre plate format to convert compound 3 into 4. HPLC was used to derive both chemical yield and stereoselectivity data that assisted the choice of optimum reaction conditions.

3 Me

(i) Catalyst

*

(ii) Oxidation

Nick Terrett Discove y Chemist y,

Pfizer Central Research Sandwich, Kent, UK

Copyright 0 Elsevler Science Ltd. All rights reserved. 1359.6446/96/$15.00 DDT Vol. 1, No. 5 May 1996